Cyclopropanamine compound and use thereof

ABSTRACT

The present invention provides a compound having a lysine-specific demethylase-1 inhibitory action, and useful as a medicament such as a prophylactic or therapeutic agent for schizophrenia, developmental disorders, particularly diseases having intellectual disability (e.g., autistic spectrum disorders, Rett syndrome, Down&#39;s syndrome, Kabuki syndrome, fragile X syndrome, Kleefstra syndrome, neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis), neurodegenerative diseases (e.g., Alzheimer&#39;s disease, Parkinson&#39;s disease, spinocerebellar degeneration (e.g., dentatorubural pallidoluysian atrophy) and Huntington&#39;s disease), epilepsy (e.g., Dravet syndrome) or drug dependence, and the like. A compound represented by the formula 
                         
wherein each symbol is as defined in the present specification, or a salt thereof.

TECHNICAL FIELD

The present invention relates to a cyclopropanamine compound having alysine-specific demethylase-1 (sometimes to be abbreviated as LSD1 inthe present specification) inhibitory action, and useful as a medicamentsuch as a prophylactic or therapeutic agent for cancer, schizophrenia,developmental disorders, particularly diseases having intellectualdisability (e.g., autistic spectrum disorders, Rett syndrome, Down'ssyndrome, Kabuki syndrome, fragile X syndrome, Kleefstra syndrome,neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis),neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson'sdisease, spinocerebellar degeneration (e.g., dentatoruburalpallidoluysian atrophy) and Huntington's disease), epilepsy (e.g.,Dravet syndrome) or drug dependence, and the like.

BACKGROUND OF THE INVENTION

LSD1 is a demethylation enzyme of histone, catalyzes a demethylationreaction of a monomethylated product and a dimethylated product of the4th lysine residue of histone H3 (H3K4me1/2), and forms formaldehyde asa by-product. In addition, LSD1 forms a complex with flavin adeninedinucleotide (FAD) which is a kind of coenzyme, and FAD promotesoxidation of lysine residue by enzymes as a redox mediator.

When a compound having a LSD1 inhibitory activity is applied to neuronalcells, histone H3 methylation especially H3K4 methylation around GAD1gene promoter is increased through inhibition of histone demethylationactivity of LSD1 (Experimental Example 3 to be mentioned later). Thereare many publications with analyses of relationship between geneexpression level and histone H3K4 methylation status, which concludethat promotion of histone H3K4 methylation at a gene promoter leads toan activated transcription of the gene (Becker, Nature 2006, 442: 31-32;Ruthenburg et al., Nature Reviews Molecular Cell Biology 2007, 8:983-994). Therefore, it is assumed that administration of a compoundhaving an LSD1 inhibitory activity accumulates histone H3K4 methylationin neurons in the brain, which in turn results in the GAD1 mRNAexpression in the brain. It is widely known that the induction of GAD1mRNA expression in the brain is effective for the treatment of centralnervous system diseases. For example, intracerebral injection of a GAD1gene expression vector to Parkinson's disease patients is known toinduce GAD1 mRNA expression and improve the symptoms of Parkinson'sdisease patients (LeWitt et al. Lancet Neurol. 2011, 10: 309-319;Carlson, Physiology of Behavior 11^(th) edition 2013). From the above,it is considered that the administration of an LSD1 inhibitor increasesthe histone H3K4 methylation and results in increase of the GAD1expression level in the brain, which may be effective for the treatmentof central nervous system diseases.

On the other hand, LSD1 also catalyzes a demethylation reaction of amethylated product of the 9th lysine residue of histone H3 (H3K9me). Adecrease of the methylation of H3K9 in animal models of some diseases,for example, animal models of cocaine dependence and Kleefstra syndromehas been reported (Science 8 Jan. 2010, 327, 213-216, Genes Dev. April2005, 19, 815-826). A decrease of the H3K9 methylation is known to causeabnormally enhanced expression of some genes. Therefore, it is assumedthat administration of a compound having an LSD1 inhibitory activityaccelerates histone H3K9 methylation in neurons in the brain, which inturn decreases the expression of genes abnormally expressed in thebrain. From the above, it is considered that LSD1 inhibitor is possiblyeffective for the treatment of some diseases with a decrease ofmethylated H3K9.

WO 2010/084160 (patent document 1) discloses a compound of the followingformula or a pharmaceutically acceptable salt thereof as an LSD1inhibitor:

wherein R1-R5 are H, halo and the like; R6 is H or alkyl; R7 is H, alkylor cycloalkyl; R8 is -L-heterocyclyl or -L-aryl wherein L is—(CH₂)_(n)—(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(n)— or —(CH₂)_(n)S(CH₂)_(n)—,and n is 0, 1, 2 or 3.

WO 2010/043721 (patent document 2) discloses a compound of the followingformula or a pharmaceutically acceptable salt thereof as an LSD1inhibitor:

wherein R1-R5 are H, halo and the like; R6 is H or alkyl; R7 is H, alkylor cycloalkyl; R8 is —C(═O)NRxRy or —C(═O)Rz wherein Rx and Ry are eachindependently H, alkyl and the like, and Rz is H, alkoxy and the like.

WO 2011/035941 (patent document 3) discloses a compound of the followingformula or a pharmaceutically acceptable salt thereof as an LSD1inhibitor:(A′)_(x)-(A)-(B)—(Z)-(L)-(D)   Iwherein (A′) is aryl, arylalkoxy, heterocyclyl and the like; (A) isheteroaryl or aryl; X is 0, 1, 2 or 3; (B) is a cyclopropyl ring; (Z) is—NH—; (L) is —CH₂CH₂— and the like; (D) is —N(—R1)-R2, —O—R3 or —S—R3wherein R1 and R2 are each independently H, alkyl and the like; and R3is H, alkyl and the like.

WO 2011/042217 (patent document 4) discloses a compound of the followingformula or a pharmaceutically acceptable salt thereof as an LSD1inhibitor:(A′)_(x)-(A)-(B)—(Z)-(L)-C(═O)NH₂   (I)wherein (A′) is aryl, arylalkoxy, arylalkyl, heterocyclyl and the like;(A) is heteroaryl or aryl; X is 0, 1, 2 or 3; (B) is a cyclopropyl ring;(Z) is —NH—; (L) is —(CH₂)_(m)CR1R2- wherein m is 0, 1, 2, 3, 4, 5 or 6;and R1 and R2 are each independently H or C1-6 alkyl.

US 2010/0324147 (patent document 5) discloses a compound of thefollowing formula or a salt thereof as an LSD1 inhibitor:

wherein X is a bond, O, S or NH; and R_(A), R_(B), R_(C), R_(D) andR_(E) are each independently H, C1-7 alkyl and the like.

WO 2010/143582 (patent document 6) discloses a compound of the followingformula or a pharmaceutically acceptable salt thereof as an LSD1inhibitor:

wherein R¹ is H, an alkyl group optionally having a substituent attachedthereto and the like; R² is an alkylene group optionally having asubstituent attached thereto; R³ is an alkyl group optionally having asubstituent attached thereto, a phenyl group optionally having asubstituent attached thereto and the like; R⁴ is an alkyl groupoptionally having a substituent attached thereto, a phenyl groupoptionally having a substituent attached thereto and the like; and X isO, NH₂, NHCO, CONH, S or CH₂.

J. Am. Chem. Soc. 2010, 132, 6827-6833 (non-patent document 1) disclosescompounds of the following formulas as an LSD 1/2 inhibitor:

WO 2012/156531 (patent document 7) discloses use of an LSD1 inhibitorfor the prophylaxis or treatment of inflammatory diseases.

WO 2012/156537 (patent document 8) discloses use of an LSD1 inhibitorfor the prophylaxis or treatment of thrombosis, thrombus formation orcirculatory diseases.

WO 2012/135113 (patent document 9) discloses, as an LSD1 inhibitor, acompound of the following formula or a pharmaceutically acceptable saltthereof:

whereinR₁ is selected from the group consisting of C₁₋₆ alkyl, —NSO₂Me,—NSO₂Ph, arylalkoxy, C₃₋₇ cycloalkyl, —NC(O)Ra,1-methyl-1H-pyrazol-4-yl, hydroxy, C₁₋₄ alkoxy, halogen, amide, amino,substituted amino and —C(O)ORa;R₂ is H or COOH;each R₃ is independently selected from the group consisting of aryl,heteroaryl, H, C₁₋₆ alkyl, —SO₂Ra, —NC(O)Ra, —CH₂C(O)ORa, —C(O)ORa,—C(O)Ra, —C(O)NRaRb, substituted amino, amino, urea, amide, sulfonamide,arylalkyl and heteroarylalkyl;each Ra is independently H, phenyl, phenylmethyl,3,5-dimethylisoxazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, C₃₋₇cycloalkyl, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₃ alkylamino or —NHPh;Rb is H or C₁₋₃ alkyl, or when attached to the same atom, Ra and Rbtogether form a 5- or 6-membered heterocycloalkyl ring;R₄ is C₁₋₄ alkyl, acyl, —C(O)CF₃ or H;W is —(CH₂)₁₋₄ or —CH(Rc) (CH₂)₀₋₃ wherein Rc is CN or C₁₋₄ alkyl;Y is N or C;X is N or C;Z is O or (CH₂)_(q) wherein q is 0-2, and when q is 0, Z is a bond;m is 0-3, n is 0-3;provided that when Z is O, Y is N and X is C;also provided that when X is C, at least one of the R₃ groups attachedto X is not H.

WO 2013/022047 (patent document 10) discloses, as an LSD1 inhibitor, thecompound of the following formula or a salt thereof.

whereinA is a hydrocarbon group optionally having substituent(s), or aheterocyclic group optionally having substituent(s);R is a hydrogen atom, a hydrocarbon group optionally havingsubstituent(s), or a heterocyclic group optionally havingsubstituent(s); orA and R are optionally bonded to each other to form a ring optionallyhaving substituent(s);Q¹, Q², Q³ and Q⁴ are each independently a hydrogen atom or asubstituent; Q¹ and Q², and Q³ and Q⁴, are each optionally bonded toeach other to form a ring optionally having substituent(s);X is a hydrogen atom, an acyclic hydrocarbon group optionally havingsubstituent(s), or a saturated cyclic group optionally havingsubstituent(s);Y¹, Y² and Y³ are each independently a hydrogen atom, a hydrocarbongroup optionally having substituent(s), or a heterocyclic groupoptionally having substituent(s);X and Y¹, and Y¹ and Y², are each optionally bonded to each other toform a ring optionally having substituent(s); andZ¹, Z² and Z³ are each independently a hydrogen atom or a substituent.

WO 2012/013727 (patent document 11) discloses, as an LSD1 inhibitor, thecompound of the following formula or a salt thereof.

wherein each symbol is as defined in patent document 11.

WO 2013/057322 (patent document 12) discloses, as an LSD1 inhibitor, thecompound of the following formula or a salt thereof.

wherein each symbol is as defined in patent document 12.

WO 2013/057320 (patent document 13) discloses, as an LSD1 inhibitor, thecompound of the following formula or a salt thereof.

wherein each symbol is as defined in patent document 13.

WO 2014/058071 (patent document 14) discloses, as an LSD1 inhibitor, thecompound of the following formula or a salt thereof.

wherein each symbol is as defined in patent document 14.

The Journal of Neuroscience, Oct. 17, 2007, 27(42): 11254-11262(non-patent document 2) discloses that a decrease in histone H3K4methylation and a decrease in Gad1 mRNA expression are observed in thebrain of schizophrenia patients. In addition, Nature Neuroscience,February 2015, 18, 199-209 (non-patent document 3) discloses that H3K4methylation pathway is deeply involved in mental diseases such asschizophrenia and the like.

MOLECULAR AND CELLULAR BIOLOGY, August 2011, 31(16), 3298-3311(non-patent document 4) discloses that LSD1 is a component of a proteincomplex that regulates transcription of beta globin and potentiallyinvolved in the suppression of transcription of beta globin. Activationof beta globin transcription is known to be useful for the treatment ofsickle cell anaemia and beta thalassemia, from which it is assumed thatLSD1 inhibition results in disinhibition of beta globin transcription,and provides a treatment effect.

DOCUMENT LIST Patent Documents

-   patent document 1: WO 2010/084160-   patent document 2: WO 2010/043721-   patent document 3: WO 2011/035941-   patent document 4: WO 2011/042217-   patent document 5: US 2010/0324147-   patent document 6: WO 2010/143582-   patent document 7: WO 2012/156531-   patent document 8: WO 2012/156537-   patent document 9: WO 2012/135113-   patent document 10: WO 2013/022047-   patent document 11: WO 2012/013727-   patent document 12: WO 2013/057322-   patent document 13: WO 2013/057320-   patent document 14: WO 2014/058071

Non-Patent Documents

-   non-patent document 1: J. Am. Chem. Soc. 2010, 132, 6827-6833-   non-patent document 2: The Journal of Neuroscience, Oct. 17, 2007,    27(42):11254-11262-   non-patent document 3: Nature Neuroscience, February 2015, 18,    199-209-   non-patent document 4: MOLECULAR AND CELLULAR BIOLOGY, August 2011,    31(16), 3298-3311

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a cyclopropanaminecompound having a superior LSD1 inhibitory action and high LSD1selectivity, and useful as a medicament such as a prophylactic ortherapeutic agent for cancer, schizophrenia, developmental disorders,particularly diseases having intellectual disability (e.g., autisticspectrum disorders, Rett syndrome, Down's syndrome, Kabuki syndrome,fragile X syndrome, Kleefstra syndrome, neurofibromatosis type 1, Noonansyndrome, tuberous sclerosis), neurodegenerative diseases (e.g.,Alzheimer's disease, Parkinson's disease, spinocerebellar degeneration(e.g., dentatorubural pallidoluysian atrophy) and Huntington's disease(Huntington chorea)), epilepsy (e.g., Dravet syndrome) or drugdependence such as cocaine dependence, and the like.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the aforementioned problems and found that a compound representedby the following formula (I) has a superior LSD1 inhibitory action andhigh LSD1 selectivity, which resulted in the completion of the presentinvention.

Accordingly, the present invention relates to the following.

[1] A compound represented by the formula

whereinA is an optionally substituted heterocyclic group, or an optionallysubstituted hydrocarbon group;B is a ring selected from(1) a 5- or 6-membered aromatic heterocycle optionally fused with anoptionally substituted 5- or 6-membered ring, and(2) a benzene ring fused with an optionally substituted 5- or 6-memberedring,wherein the ring represented by B is optionally substituted, and binds,via two adjacent carbon atoms with one atom in between, to a grouprepresented by the formula

anda group represented by the formula

R¹, R², R³ and R⁴ are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group or an optionally substituted heterocyclicgroup;A and R¹ are optionally bonded with each other to form, together withthe adjacent nitrogen atom, an optionally substituted cyclic group; andR² and R³ are optionally bonded with each other to form, together withthe adjacent nitrogen atom, an optionally substituted cyclic group,or a salt thereof (hereinafter to be also referred to as compound (I)).[2] The compound of [1], wherein A is(1) an optionally substituted heterocyclic group, or(2) an optionally substituted C₃₋₁₀ cycloalkyl group, or a salt thereof.[3] The compound of [1] or [2], wherein B is a ring selected from(1) a 5- or 6-membered aromatic heterocycle, and(2) a benzene ring fused with an optionally substituted 5- or 6-memberedring,wherein the ring represented by B is optionally substituted, and binds,via two adjacent carbon atoms with one atom in between, to a grouprepresented by the formula (II), and a group represented by the formula(III),or a salt thereof.[4] The compound of [1], [2] or [3], wherein, in the formula

B is a ring selected from

whereinX¹, X², X³ and X⁴ are each independently a carbon atom or a nitrogenatom;at least one of X¹, X², X³ and X⁴ is a nitrogen atom;Y¹, Y² and Y³ are each independently a carbon atom, a nitrogen atom, anoxygen atom or a sulfur atom;at least one of Y¹, Y² and Y³ is a nitrogen atom, an oxygen atom or asulfur atom; andZ¹, Z², Z³ and Z⁴ are each independently a carbon atom or a nitrogenatom, which ring is optionally substituted, or a salt thereof.[5] The compound of [1], [2], [3] or [4], wherein R, R² and R⁴ are eachindependently a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup,or a salt thereof.[6] The compound of [1], [2], [3], [4] or [5], wherein R³ is(1) a hydrogen atom,(2) an optionally substituted C₁₋₆ alkyl group,(3) an optionally substituted C₃₋₁₀ cycloalkyl group, or(4) an optionally substituted heterocyclic group,or a salt thereof.[7] The compound of [1], wherein, in the formula

A is(1) (i) a 5- or 6-membered aromatic heterocyclic group or (ii) a 4- to6-membered non-aromatic heterocyclic group, each of which is optionallysubstituted by C₁₋₆ alkyl group(s) optionally substituted by halogenatom(s), or(2) a C₃₋₁₀ cycloalkyl group optionally substituted by halogen atom(s);B is a ring selected from

whereinX¹, X², X³ and X⁴ are each independently a carbon atom or a nitrogenatom;at least one of X¹, X², X³ and X⁴ is a nitrogen atom;Y¹, Y² and Y³ are each independently a carbon atom, a nitrogen atom, anoxygen atom or a sulfur atom;at least one of Y¹, Y² and Y³ is a nitrogen atom, an oxygen atom or asulfur atom; andZ¹, Z², Z³ and Z⁴ are each independently a carbon atom or a nitrogenatom, which ring is optionally substituted by C₁₋₆ alkyl group(s);R¹ is a hydrogen atom;R² is a hydrogen atom;R³ is(1) a hydrogen atom,(2) a C₁₋₆ alkyl group optionally substituted by substituent(s) selectedfrom

-   -   (a) a C₃₋₁₀ cycloalkyl group,    -   (b) a C₆₋₁₄ aryl group optionally substituted by carboxy        group(s),    -   (c) a 4- to 6-membered non-aromatic heterocyclic group        optionally substituted by C₁₋₆ alkyl group(s) optionally        substituted by substituent(s) selected from a carboxy group, and        a C₆₋₁₄ aryl group optionally substituted by carboxy group(s),        and    -   (d) a 5- or 6-membered aromatic heterocyclic group optionally        substituted by amino group(s),        (3) a C₃₋₁₀ cycloalkyl group optionally substituted by        substituent(s) selected from an amino group and a halogen atom        or        (4) a 4- to 6-membered non-aromatic heterocyclic group        optionally substituted by substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by halogen        atom(s),    -   (b) a C₃₋₁₀ cycloalkyl group,    -   (c) a C₁₋₆ alkyl-carbonyl group, and    -   (d) a C₃₋₁₀ cycloalkyl-carbonyl group; and        R⁴ is a hydrogen atom,        or a salt thereof.        [7A] The compound of [1], wherein A is        (1) (i) a 5- or 6-membered aromatic heterocyclic group or (ii) a        4- to 6-membered non-aromatic heterocyclic group, each of which        is optionally substituted by C₁₋₆ alkyl group(s) optionally        substituted by halogen atom(s), or        (2) a C₃₋₁₀ cycloalkyl group optionally substituted by halogen        atom(s);        B is a ring selected from        thiophene, thiazole, pyrazole, pyridine, naphthalene and        2,3-dihydrobenzofuran, wherein the ring is optionally        substituted by C₁₋₆ alkyl group(s);        R¹ is a hydrogen atom;        R² is a hydrogen atom;        R³ is        (1) a hydrogen atom,        (2) a C₁₋₆ alkyl group optionally substituted by substituent(s)        selected from    -   (a) a C₃₋₁₀ cycloalkyl group,    -   (b) a C₆₋₁₄ aryl group optionally substituted by carboxy        group(s),    -   (c) a 4- to 6-membered non-aromatic heterocyclic group        optionally substituted by C₁₋₆ alkyl group(s) optionally        substituted by substituent(s) selected from a carboxy group, and        a C₆₋₁₄ aryl group optionally substituted by carboxy group(s),        and    -   (d) a 5- or 6-membered aromatic heterocyclic group optionally        substituted by amino group(s),        (3) a C₃₋₁₀ cycloalkyl group optionally substituted by        substituent(s) selected from an amino group and a halogen atom        or        (4) a 4- to 6-membered non-aromatic heterocyclic group        optionally substituted by substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by halogen        atom(s),    -   (b) a C₃₋₁₀ cycloalkyl group,    -   (c) a C₁₋₆ alkyl-carbonyl group, and    -   (d) a C₃₋₁₀ cycloalkyl-carbonyl group; and        R⁴ is a hydrogen atom,        or a salt thereof.        [8] The compound of [1], wherein A is        (1) a piperidinyl group, an isoxazolyl group, a pyrazolyl group,        a thiadiazolyl group, a thiazolyl group, a tetrahydropyranyl        group, an oxetanyl group, an oxadiazolyl group, a thienyl group,        a pyridyl group or an oxazolyl group, each of which is        optionally substituted by C₁₋₆ alkyl group(s) optionally        substituted by halogen atom(s), or        (2) a C₃₋₁₀ cycloalkyl group optionally substituted by halogen        atom(s);        B is a ring selected from        thiophene, thiazole, pyrazole, pyridine, naphthalene and        2,3-dihydrobenzofuran, wherein the ring is optionally        substituted by C₁₋₆ alkyl group(s);        R¹ is a hydrogen atom;        R² is a hydrogen atom;        R³ is        (1) a hydrogen atom,        (2) a C₁₋₆ alkyl group optionally substituted by substituent(s)        selected from    -   (a) a C₃₋₁₀ cycloalkyl group,    -   (b) a C₆₋₁₄ aryl group optionally substituted by carboxy        group(s),    -   (c) a tetrahydropyranyl group or a piperidinyl group each        optionally substituted by C₁₋₆ alkyl group(s) optionally        substituted by substituent(s) selected from a carboxy group, and        a C₆₋₁₄ aryl group optionally substituted by carboxy group(s),        and    -   (d) an oxadiazolyl group optionally substituted by an amino        group,        (3) a C₃₋₁₀ cycloalkyl group optionally substituted by        substituent(s) selected from an amino group and a halogen atom        or        (4) a tetrahydropyranyl group or a piperidinyl group each        optionally substituted by substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by halogen        atom(s),    -   (b) a C₃₋₁₀ cycloalkyl group,    -   (c) a C₁₋₆ alkyl-carbonyl group, and    -   (d) a C₃₋₁₀ cycloalkyl-carbonyl group; and        R⁴ is a hydrogen atom,        or a salt thereof.        [8A] The compound of [1], wherein A is        (1) a piperidinyl group, an isoxazolyl group, a pyrazolyl group,        a thiadiazolyl group, a thiazolyl group, a tetrahydropyranyl        group, an oxetanyl group, an oxadiazolyl group, a thienyl group,        a pyridyl group or an oxazolyl group, each of which is        optionally substituted by C₁₋₆ alkyl group(s) (preferably, 1 or        2 C₁₋₆ alkyl groups) optionally substituted by halogen atom(s)        (preferably, 1 to 3 halogen atoms), or        (2) a cyclopropyl group, a cyclobutyl group, a cyclopentyl group        or a cyclohexyl group, each of which is optionally substituted        by halogen atom(s) (preferably, 1 or 2 halogen atoms);        B is a ring selected from        thiophene, thiazole, pyrazole, pyridine, naphthalene and        2,3-dihydrobenzofuran, wherein the ring is optionally        substituted by C₁₋₆ alkyl group(s) (preferably, one C16 alkyl        group);        R¹ is a hydrogen atom;        R² is a hydrogen atom;        R³ is        (1) a hydrogen atom,        (2) a C₁₋₆ alkyl group optionally substituted by substituent(s)        (preferably, one substituent) selected from    -   (a) a cyclopropyl group or cyclobutyl group,    -   (b) a phenyl group optionally substituted by carboxy group(s)        (preferably, one carboxy group),    -   (c) a tetrahydropyranyl group or a piperidinyl group each        optionally substituted by C₁₋₆ alkyl group(s) (preferably, one        C₁₋₆ alkyl group) optionally substituted by substituent(s)        (preferably, one substituent) selected from a carboxy group, and        a phenyl group optionally substituted by carboxy group(s)        (preferably, one carboxy group), and    -   (d) an oxadiazolyl group optionally substituted by an amino        group (one amino group),        (3) a cyclobutyl group or a cyclohexyl group each optionally        substituted by substituent(s) (preferably, 1 or 2 substituents)        selected from an amino group and a halogen atom, or        (4) a tetrahydropyranyl group or a piperidinyl group each        optionally substituted by substituent(s) (preferably, one        substituent) selected from    -   (a) a C₁₋₆ alkyl group optionally substituted by halogen atom(s)        (preferably, 1 to 3 halogen atoms),    -   (b) a cyclopropyl group,    -   (c) a C₁₋₆ alkyl-carbonyl group, and    -   (d) a cyclopropyl-carbonyl group; and        R⁴ is a hydrogen atom,        or a salt thereof.        [9] The compound of [1], wherein A is        (1) a pyrazolyl group, a thiadiazolyl group or a        tetrahydropyranyl group, each optionally substituted by C₁₋₆        alkyl group(s) (preferably, 1 or 2 C₁₋₆ alkyl groups), or        (2) a cyclohexyl group optionally substituted by halogen atom(s)        (preferably, 1 or 2 halogen atoms);        B is        a thiophene ring, which ring is optionally substituted by C₁₋₆        alkyl group(s) (preferably, one C₁₋₆ alkyl group);        R¹ is a hydrogen atom;        R² is a hydrogen atom;        R³ is a cyclopropylmethyl group, a tetrahydropyranylmethyl        group, a cyclobutylmethyl group, a cyclobutyl group or a        tetrahydropyranyl group; and        R⁴ is a hydrogen atom,        or a salt thereof.        [9A] The compound of [1], wherein A is        a pyrazolyl group, a thiadiazolyl group or a tetrahydropyranyl        group, each optionally substituted by C₁₋₆ alkyl group(s)        (preferably, one C₁₋₆ alkyl group),        B is        a thiophene ring, which ring is optionally substituted by C₁₋₆        alkyl group(s) (preferably, one C₁₋₆ alkyl group);        R¹ is a hydrogen atom;        R² is a hydrogen atom;        R³ is a cyclopropylmethyl group, a tetrahydropyranylmethyl group        or a cyclobutyl group; and        R⁴ is a hydrogen atom,        or a salt thereof.        [10] The compound of [1], wherein A is        a pyrazolyl group, a thiadiazolyl group or a tetrahydropyranyl        group, each optionally substituted by C₁₋₆ alkyl group(s)        (preferably, one C₁₋₆ alkyl group),        B is        a thiophene ring, which ring is optionally substituted by C₁-6        alkyl group(s) (preferably, one C₁₋₆ alkyl group);        R¹ is a hydrogen atom;        R² is a hydrogen atom;        R³ is a cyclopropylmethyl group or a cyclobutyl group; and        R⁴ is a hydrogen atom,        or a salt thereof.        [11]        5-((1R,2R)-2-((Cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide        or a salt thereof.        [12]        4-((1S,2R)-2-(Cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide        or a salt thereof.        [13]        4-((1S,2R)-2-(Cyclobutylamino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide        or a salt thereof.        [14] A medicament comprising the compound of any one of [1] to        [13], [7A], [8A] and [9A] or a salt thereof.        [15] The medicament of [14], which is an LSD1 inhibitor.        [15A] The medicament of [14], which is a prophylactic or        therapeutic agent for schizophrenia, Alzheimer's disease,        Parkinson's disease or Huntington's disease (Huntington chorea).        [16] The medicament of [14], which is a prophylactic or        therapeutic agent for schizophrenia, developmental disorders,        autistic spectrum disorders, Rett syndrome, Down's syndrome,        Kabuki syndrome, fragile X syndrome, Kleefstra syndrome,        neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis,        Alzheimer's disease, Parkinson's disease, spinocerebellar        degeneration, Huntington's disease, epilepsy or drug dependence.        [17] The compound of any one of [1] to [13], [7A], [8A] and [9A]        or a salt thereof for use in the prophylaxis or treatment of        schizophrenia, developmental disorders, autistic spectrum        disorders, Rett syndrome, Down's syndrome, Kabuki syndrome,        fragile X syndrome, Kleefstra syndrome, neurofibromatosis type        1, Noonan syndrome, tuberous sclerosis, Alzheimer's disease,        Parkinson's disease, spinocerebellar degeneration, Huntington's        disease, epilepsy or drug dependence.        [18] A method of inhibiting LSD1 in a mammal, comprising        administering an effective amount of the compound of any one of        [1] to [13], [7A], [8A] and [9A] or a salt thereof to the        mammal.        [19] A method for the prophylaxis or treatment of schizophrenia,        developmental disorders, autistic spectrum disorders, Rett        syndrome, Down's syndrome, Kabuki syndrome, fragile X syndrome,        Kleefstra syndrome, neurofibromatosis type 1, Noonan syndrome,        tuberous sclerosis, Alzheimer's disease, Parkinson's disease,        spinocerebellar degeneration, Huntington's disease, epilepsy or        drug dependence in a mammal, comprising administering an        effective amount of the compound of any one of [1] to [13],        [7A], [8A] and [9A] or a salt thereof to the mammal.        [20] Use of the compound of any one of [1] to [13], [7A], [8A]        and [9A] or a salt thereof in the production of a prophylactic        or therapeutic agent for schizophrenia, developmental disorders,        autistic spectrum disorders, Rett syndrome, Down's syndrome,        Kabuki syndrome, fragile X syndrome, Kleefstra syndrome,        neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis,        Alzheimer's disease, Parkinson's disease, spinocerebellar        degeneration, Huntington's disease, epilepsy or drug dependence.        [7B] The compound of [4], wherein B is a ring represented by the        formula

whereinY¹, Y² and Y³ are each independently a carbon atom, a nitrogen atom, anoxygen atom or a sulfur atom; andat least one of Y¹, Y² and Y³ is a nitrogen atom, an oxygen atom or asulfur atom, which ring is optionally substituted, or a salt thereof.[8B] The compound of [1], wherein B is a ring selected from thiopheneand thiazole, and the ring is optionally substituted, or a salt thereof.[9B] The compound of [1], [7B] or [8B], wherein R² is a hydrogen atomand R³ is a cyclopropylmethyl group, or a salt thereof.[10B] The compound of [1], [7B] or [5B], wherein R² is a hydrogen atomand R³ is a cyclobutyl group, or a salt thereof.[11B] The compound of [1], [7B] or [8B], wherein R² is a hydrogen atomand R³ is a tetrahydropyranyl group, or a salt thereof.[12B] The compound of [1], [7B] or [8B], wherein R² is a hydrogen atomand R³ is a tetrahydropyranylmethyl group, or a salt thereof.[13B] The compound of [1], [7B] or [8B], wherein R² is a hydrogen atomand R³ is an optionally substituted piperidinyl group (preferably, apiperidinyl group optionally substituted by one C₁₋₆ alkyl groupoptionally substituted by 1 to 3 halogen atoms), or a salt thereof.[14B] The compound of any one of [1] and [7B] to [13B], wherein R¹ is ahydrogen atom, or a salt thereof.[15B] The compound of any one of [1] and [7B] to [14B], wherein A is(1) a piperidinyl group, an isoxazolyl group, a pyrazolyl group, athiadiazolyl group, a thiazolyl group or a tetrahydropyranyl group, eachoptionally substituted by C₁₋₆ alkyl group(s) (preferably, one C₁₋₆alkyl group) optionally substituted by halogen atom(s) (preferably, 1 to3 halogen atoms), or(2) a cyclopentyl group or a cyclohexyl group, each optionallysubstituted by halogen atom(s) (preferably, 1 or 2 halogen atoms), or asalt thereof.

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, l-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₁₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, l-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

[Substituent Group A]

(1) a halogen atom,

(2) a nitro group,

(3) a cyano group,

(4) an oxo group,

(5) a hydroxy group,

(6) an optionally halogenated C₁₋₆ alkoxy group,

(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),

(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),

(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),

(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),

(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),

(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),

(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),

(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),

(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),

(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),

(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),

(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

(20) an optionally halogenated C₁₋₆ alkylthio group,

(21) a 5- to 14-membered aromatic heterocyclic group,

(22) a 3- to 14-membered non-aromatic heterocyclic group,

(23) a formyl group,

(24) a carboxy group,

(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,

(26) a C₆₋₁₄ aryl-carbonyl group,

(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,

(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,

(29) a C₁₋₆ alkoxy-carbonyl group,

(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),

(32) a carbamoyl group,

(33) a thiocarbamoyl group,

(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),

(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),

(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),

(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,

(39) a C₆₋₁₄ arylsulfonyl group,

(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),

(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,

(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),

(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),

(44) an amino group,

(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),

(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),

(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),

(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),

(49) a formylamino group,

(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),

(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,N-acetyl-N-methylamino),

(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),

(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),

(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),

(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),

(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),

(57) an optionally halogenated C₁₋₆ alkyl group,

(58) a C₂₋₆ alkenyl group,

(59) a C₂₋₆ alkynyl group,

(60) a C₃₋₁₀ cycloalkyl group,

(61) a C₃₋₁₀ cycloalkenyl group and

(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,f-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-3-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl)aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a(C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl)amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁-6 alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₁₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₁₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₀₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl)

In the present specification, examples of the “5- or 6-membered aromaticheterocycle” include a 5- or 6-membered aromatic heterocycle containing,as a ring-constituting atom besides carbon atoms, 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.Preferable examples of the “5- or 6-membered aromatic heterocycle”include 5- or 6-membered aromatic heterocycles such as thiophene, furan,pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole,triazine and the like.

A is an optionally substituted heterocyclic group, or an optionallysubstituted hydrocarbon group.

A is preferably

(1) an optionally substituted heterocyclic group, or

(2) an optionally substituted C₃₋₁₀ cycloalkyl group.

A is more preferably

(1) a heterocyclic group (preferably, (i) a 5- or 6-membered aromaticheterocyclic group or (ii) a 4- to 6-membered non-aromatic heterocyclicgroup, each containing, as a ring-constituting atom besides carbonatoms, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atomand an oxygen atom) (e.g., piperidinyl group, isoxazolyl group,pyrazolyl group, thiadiazolyl group, thiazolyl group, tetrahydropyranylgroup, oxetanyl group, oxadiazolyl group, thienyl group, pyridyl group,oxazolyl group) optionally substituted by C₁₋₆ alkyl group(s)(preferably, 1 or 2 C₁₋₆ alkyl groups) optionally substituted by halogenatom(s) (preferably, 1 to 3 halogen atoms), or(2) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group) optionally substituted by halogenatom(s) (preferably, 1 or 2 halogen atoms).

A is more preferably

(1) a piperidinyl group, an isoxazolyl group, a pyrazolyl group, athiadiazolyl group, a thiazolyl group or a tetrahydropyranyl group, eachoptionally substituted by C₁₋₆ alkyl group(s) (preferably, one C₁₋₆alkyl group) optionally substituted by halogen atom(s) (preferably, 1 to3 halogen atoms), or(2) a cyclopentyl group or a cyclohexyl group, each optionallysubstituted by halogen atom(s) (preferably, 1 or 2 halogen atoms).

A is particularly preferably

(1) a pyrazolyl group, a thiadiazolyl group or a tetrahydropyranylgroup, each optionally substituted by C₁₋₆ alkyl group(s) (preferably,one C₁₋₆ alkyl group), or

(2) a cyclopentyl group or a cyclohexyl group, each optionallysubstituted by halogen atom(s) (preferably, 1 or 2 halogen atoms).

B is a ring selected from

(1) a 5- or 6-membered aromatic heterocycle optionally fused with anoptionally substituted 5- or 6-membered ring, and

(2) a benzene ring fused with an optionally substituted 5- or 6-memberedring,

and the ring represented by B is optionally substituted and binds, viatwo adjacent carbon atoms with one atom in between, to a grouprepresented by the formula

and a group represented by the formula

Examples of the “optionally substituted 5- or 6-membered ring” include a5- or 6-membered ring optionally having substituent(s) selected from theaforementioned substituent group A.

The number of the substituents for the “optionally substituted 5- or6-membered ring” is, for example, 1 to 3. When the number of thesubstituents is two or more, respective substituents may be the same ordifferent.

The substituent that B optionally has is, for example, a substituentselected from the aforementioned substituent group A.

The number of the substituents that B optionally has is, for example, 1to 3, preferably 1 or 2, more preferably 1. When the number of thesubstituents is two or more, respective substituents may be the same ordifferent.

B is preferably a ring selected from

(1) a 5- or 6-membered aromatic heterocycle, and

(2) a benzene ring fused with an optionally substituted 5- or 6-memberedring,

and the ring represented by B is optionally substituted, via twoadjacent carbon atoms with one atom in between, and binds to a grouprepresented by the formula (II), and a group represented by the formula(III).

In the formula

B is more preferably, a ring selected from

whereinX¹, X², X³ and X⁴ are each independently a carbon atom or a nitrogenatom;at least one of X¹, X², X³ and X⁴ is a nitrogen atom;Y¹, Y² and Y³ are each independently a carbon atom, a nitrogen atom, anoxygen atom or a sulfur atom;at least one of Y¹, Y² and Y³ is a nitrogen atom, an oxygen atom or asulfur atom; andZ¹, Z², Z³ and Z⁴ are each independently a carbon atom or a nitrogenatom, which ring is optionally substituted.

Preferable examples of B include a ring selected from

The ring is optionally substituted by 1 or 2 (preferably 1) C₁₋₆ alkylgroups.

B is more preferably a ring represented by the formula

whereinY¹, Y² and Y³ are each independently a carbon atom, a nitrogen atom, anoxygen atom or a sulfur atom; andat least one of Y¹, Y² and Y³ is a nitrogen atom, an oxygen atom or asulfur atom, and the ring is optionally substituted.

B is particularly preferably a ring selected from thiophene andthiazole, and the ring is optionally substituted.

Another preferable embodiment of B is thiophene or thiazole eachoptionally substituted by 1 or 2 (preferably 1) C₁₋₆ alkyl groups.

A still another preferable embodiment of B is thiophene optionallysubstituted by one C₁₋₆ alkyl group.

A yet another preferable embodiment of B is

wherein R⁷ is a hydrogen atom or a C₁₋₆ alkyl group.

R¹, R², R³ and R⁴ are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group or an optionally substituted heterocyclicgroup.

R¹ is preferably a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, more preferably, a hydrogen atom or a C₁₋₆ alkyl group,particularly preferably a hydrogen atom.

A and R¹ are optionally bonded with each other to form, together withthe adjacent nitrogen atom optionally substituted cyclic group.

Examples of the “cyclic group” of the “optionally substituted cyclicgroup”, which is formed, together with the adjacent nitrogen atom, by Aand R¹ bonded to each other include a 4- to 10-membered heterocyclicgroup containing one nitrogen atom as a ring-constituting atom besidescarbon atom, and optionally further containing one hetero atom selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom, and the like.Examples of the “4- to 10-membered heterocyclic group” includeazetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrazolin-1-yl,imidazolin-1-yl, thiazolidin-3-yl, oxazolidin-3-yl, isothiazolidin-2-yl,isoxazolidin-2-yl, thiazolin-3-yl, oxazolin-3-yl, isothiazolin-2-yl,isoxazolin-2-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, azepan-1-yl, diazepan-1-yl, 1,4-oxazepan-4-yl,1,4-thiazepan-4-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl and thelike.

Examples of the substituent of the “optionally substituted cyclicgroup”, which is formed, together with the adjacent nitrogen atom, by Aand R¹ bonded to each other, include substituents selected from theaforementioned substituent group A.

The number of the substituents in “optionally substituted cyclic group”,which is formed, together with the adjacent nitrogen atom, by A and R¹bonded to each other, is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

Preferable examples of the “optionally substituted cyclic group”, whichis formed, together with the adjacent nitrogen atom, by A and R¹ bondedto each other include a 4 to 10-membered heterocyclic group containingone nitrogen atom as a ring-constituting atom besides carbon atoms, andoptionally further containing one hetero atom selected from a nitrogenatom, a sulfur atom and an oxygen atom (e.g., azetidin-1-yl,pyrrolidin-1-yl, piperidin-1-yl,5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl), and the heterocyclic groupis optionally substituted by 1 to 3 substituents selected from a hydroxygroup and a cyano group,

As regards —N(R′) (A) moiety,

R¹ is preferably a hydrogen atom.

A is preferably

(1) a piperidinyl group, an isoxazolyl group, a pyrazolyl group, athiadiazolyl group, a thiazolyl group or a tetrahydropyranyl group eachoptionally substituted by C₁₋₆ alkyl group(s) (preferably, one C₁₋₆alkyl group) optionally substituted by halogen atom(s) (preferably, 1 to3 halogen atoms), or(2) a cyclopentyl group or a cyclohexyl group each optionallysubstituted by halogen atom(s) (preferably, 1 or 2 halogen atoms).

R² is preferably a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, more preferably, a hydrogen atom or a C₁₋₆ alkyl group,particularly preferably a hydrogen atom.

R³ is preferably

(1) a hydrogen atom,

(2) an optionally substituted C₁₋₆ alkyl group,

(3) an optionally substituted C₃₋₁₀ cycloalkyl group, or

(4) an optionally substituted heterocyclic group.

R³ is more preferably

(1) a hydrogen atom,

(2) a C₁₋₆ alkyl group substituted by one C₃₋₁₀ cycloalkyl group (e.g.,cyclopropylmethyl group),

(3) a C₁₋₆ alkyl group substituted by one 4- to 6-membered non-aromaticheterocyclic group (preferably, a 4- to 6-membered non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atoms, 1 or 2 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom) (e.g., tetrahydropyranylmethyl group),(4) a C₃₋₁₀ cycloalkyl group (e.g., cyclobutyl group, cyclohexyl group)optionally substituted by one amino group, or(5) a 4- to 6-membered non-aromatic heterocyclic group (preferably, a 4-to 6-membered non-aromatic heterocyclic group containing, as aring-constituting atom besides carbon atoms, 1 or 2 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom) (e.g.,tetrahydropyranyl group, piperidinyl group), and the heterocyclic groupis optionally substituted by one substituent selected from

-   -   (a) a C₁₋₆ alkyl group optionally substituted by halogen atom(s)        (preferably, 1 to 3 halogen atoms), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl group).

R³ is more preferably a hydrogen atom, a cyclopropylmethyl group, atetrahydropyranylmethyl group, a cyclobutyl group or a tetrahydropyranylgroup.

R³ is particularly preferably a cyclopropylmethyl group, atetrahydropyranylmethyl group, a cyclobutyl group or a tetrahydropyranylgroup.

R² and R³ are optionally bonded with each other to form, together withthe adjacent nitrogen atom, an optionally substituted cyclic group.

Examples of the “cyclic group” of the “optionally substituted cyclicgroup”, which is formed, together with the adjacent nitrogen atom, by R²and R³ bonded to each other include a 4- to 10-membered heterocyclicgroup containing one nitrogen atom as a ring-constituting atom besidescarbon atom, and optionally further containing one hetero atom selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom, and the like.Examples of the “4- to 10-membered heterocyclic group” includeazetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrazolin-1-yl,imidazolin-1-yl, thiazolidin-3-yl, oxazolidin-3-yl, isothiazolidin-2-yl,isoxazolidin-2-yl, thiazolin-3-yl, oxazolin-3-yl, isothiazolin-2-yl,isoxazolin-2-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, azepan-1-yl, diazepan-1-yl, 1,4-oxazepan-4-yl,1,4-thiazepan-4-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl and thelike.

Examples of the substituent of the “optionally substituted cyclicgroup”, which is formed, together with the adjacent nitrogen atom, by R²and R³ bonded to each other include substituents selected from theaforementioned substituent group A.

The number of the substituents in “optionally substituted cyclic group”,which is formed, together with the adjacent nitrogen atom, by R² and R³bonded to each other is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

Preferable examples of the “optionally substituted cyclic group”, whichis formed, together with the adjacent nitrogen atom, by R² and R³ bondedto each other include a 4- to 10-membered heterocyclic group containingone nitrogen atom as a ring-constituting atom besides carbon atom, andoptionally further containing one hetero atom selected from a nitrogenatom, a sulfur atom and an oxygen atom (e.g., pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl), and theheterocyclic group is optionally substituted by 1 to 3 oxo groups.

A preferable combination of R² and R³ is

-   -   a hydrogen atom and a cyclopropylmethyl group,    -   a hydrogen atom and a cyclobutyl group,    -   a hydrogen atom and a tetrahydropyranyl group,    -   a hydrogen atom and a tetrahydropyranylmethyl group, or    -   a hydrogen atom and an optionally substituted piperidinyl group        (preferably, a piperidinyl group optionally substituted by one        C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms).

R⁴ is preferably a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, more preferably, a hydrogen atom or a C₁₋₆ alkyl group,particularly preferably a hydrogen atom.

In the formula (I), the relative configuration of the substituentrepresented by the formula (R¹) (A)N—CO—B— and the substituentrepresented by the formula —N(R²) (R³) on the cyclopropane ring is cisor trans, preferably trans.

A compound of the formula (I) having a preferable relative configurationis shown by the following formula (IA).

Relative Configuration

wherein A, B, R¹, R², R³ and R⁴ are as defined above.

Compound (I) encompasses a compound having the absolute configurationrepresented by the following formula (IB) or (IC), and a mixture thereofat any ratio.

Absolute Configuration

wherein A, B, R¹, R², R³ and R⁴ are as defined above.

Preferable examples of compound (I) include the following compounds.

[Compound A]

Compound (I) wherein

B is a ring selected from thiophene, thiazole, pyrazole, pyridine,naphthalene and 2,3-dihydrobenzofuran, and the ring is optionallysubstituted by C₁₋₆ alkyl group(s) (preferably, one C₁₋₆ alkyl group);

A is

(1) a heterocyclic group (preferably, (i) a 5- or 6-membered aromaticheterocyclic group or (ii) a 4- to 6-membered non-aromatic heterocyclicgroup, each containing, as a ring-constituting atom besides carbonatoms, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atomand an oxygen atom) (e.g., piperidinyl group, isoxazolyl group,pyrazolyl group, thiadiazolyl group, thiazolyl group, tetrahydropyranylgroup, oxetanyl group, oxadiazolyl group, thienyl group, pyridyl group,oxazolyl group) optionally substituted by C₁₋₆ alkyl group(s)(preferably, 1 or 2 C₁₋₆ alkyl groups) optionally substituted by halogenatom(s) (preferably, 1 to 3 halogen atoms) or(2) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group) optionally substituted by halogenatom(s) (preferably, 1 or 2 halogen atoms);R¹ is a hydrogen atom;R² is a hydrogen atom;R³ is(1) a hydrogen atom,(2) a C₁₋₆ alkyl group substituted by one C₃₋₁₀ cycloalkyl group (e.g.,cyclopropylmethyl group),(3) a C₁₋₆ alkyl group substituted by one 4- to 6-membered non-aromaticheterocyclic group (preferably, a 4- to 6-membered non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atoms, 1 or 2 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom) (e.g., tetrahydropyranylmethyl group),(4) a C₃₋₁₀ cycloalkyl group (e.g., cyclobutyl group, cyclohexyl group)optionally substituted by one amino group, or(5) a 4- to 6-membered non-aromatic heterocyclic group (preferably, a 4-to 6-membered non-aromatic heterocyclic group containing, as aring-constituting atom besides carbon atoms, 1 or 2 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom) (e.g.,tetrahydropyranyl group, piperidinyl group) optionally substituted byone substituent selected from

-   -   (a) a C₁₋₆ alkyl group optionally substituted by halogen atom(s)        (preferably, 1 to 3 halogen atoms), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl group); and        R⁴ is a hydrogen atom.        [Compound B]

Compound (I) wherein

B is a ring selected from

thiophene, thiazole, pyrazole, pyridine, naphthalene and2,3-dihydrobenzofuran, wherein the ring is optionally substituted byC₁₋₆ alkyl group(s) (preferably, one C₁₋₆ alkyl group); A is

(1) a pyrazolyl group, a thiadiazolyl group or a tetrahydropyranylgroup, each optionally substituted by C₁₋₆ alkyl group(s) (preferably,one C₁₋₆ alkyl group), or

(2) a cyclopentyl group or a cyclohexyl group, each optionallysubstituted by halogen atom(s) (preferably, 1 or 2 halogen atoms);

R¹ is a hydrogen atom;

R² is a hydrogen atom;

R³ is a hydrogen atom, a cyclopropylmethyl group, atetrahydropyranylmethyl group, a cyclobutyl group or a tetrahydropyranylgroup; and

R⁴ is a hydrogen atom.

[Compound C]

Compound (I) wherein

B is a ring selected from thiophene and thiazole, and the ring isoptionally substituted by C₁₋₆ alkyl group(s) (preferably, one C₁₋₆alkyl group);

A is

(1) a pyrazolyl group, a thiadiazolyl group or a tetrahydropyranylgroup, each optionally substituted by C₁₋₆ alkyl group(s) (preferably,one C₁₋₆ alkyl group, or

(2) a cyclopentyl group or a cyclohexyl group, each optionallysubstituted by halogen atom(s) (preferably, 1 or 2 halogen atoms);

R¹ is a hydrogen atom;

R² is a hydrogen atom;

R³ is a cyclopropylmethyl group, a tetrahydropyranylmethyl group, acyclobutyl group or a tetrahydropyranyl group; and

R⁴ is a hydrogen atom.

[Compound D]

A compound represented by the formula (IA)

wherein A, B, R¹, R², R³ and R⁴ are as defined for compound A, and thesteric configuration shows a relative configuration, or a salt thereof.[Compound E]

A compound represented by the formula (IA)

wherein A, B, R¹, R², R³ and R⁴ are as defined for compound B, and thesteric configuration shows a relative configuration, or a salt thereof.[Compound F]

A compound represented by the formula (IA)

wherein A, B, R¹, R², R³ and R⁴ are as defined for compound C, and thesteric configuration shows a relative configuration, or a salt thereof.

The salt of compound (I) is preferably a pharmacologically acceptablesalt. Examples of such salt include salts with inorganic bases, saltswith organic bases, salts with inorganic acids, salts with organicacids, and salts with basic or acidic amino acids.

Preferable examples of salts with inorganic bases include alkali metalsalts such as sodium salts, potassium salts and the like; alkali earthmetal salts such as calcium salts, magnesium salts and the like;aluminum salts; and ammonium salts.

Preferable examples of salts with organic bases include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine and the like.

Preferable examples of salts with inorganic acids include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferable examples of salts with organic acids include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidand the like.

Preferable examples of salts with basic amino acids include salts witharginine, lysine, ornithine and the like.

Preferable examples of salts with acidic amino acids include salts withaspartic acid, glutamic acid and the like.

The salt of compound (I) is preferably a salt with an inorganic acid(preferably, hydrochloric acid) or an organic acid (preferably,trifluoroacetic acid).

Compound (I) may also be used as a prodrug. A prodrug of compound (I)means a compound which is converted to compound (I) due to a reactiondue to an enzyme, gastric acid, etc. under the physiological conditionin the living body, that is, a compound which is converted to compound(I) with oxidation, reduction, hydrolysis, and the like according to anenzyme; a compound which is converted to compound (I) by hydrolysis etc.due to gastric acid, and the like. A prodrug for compound (I) may be acompound obtained by subjecting an amino group in compound (I) to anacylation, alkylation or phosphorylation (e.g., a compound obtained bysubjecting an amino group in compound (I) to an eicosanoylation,alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting a hydroxy group incompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation anddimethylaminomethylcarbonylation); a compound obtained by subjecting acarboxyl group in compound (I) to an esterification or amidation (e.g.,a compound obtained by subjecting a carboxyl group in compound (I) to anethyl esterification, phenyl esterification, carboxymethylesterification, dimethylaminomethyl esterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethyl esterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification and methylamidation) and thelike. Any of these compounds can be produced from compound (I) by amethod known per se.

The prodrug of compound (I) may be a compound that converts to compound(I) under physiological conditions as described in Development ofPharmaceutical Products, vol. 7, Molecular Design, 163-198, HirokawaShoten (1990).

Compound (I) may be labeled with an isotope (e.g., ²H, ³H, ¹⁴C, ³⁵S,¹²⁵I, ¹¹C, ¹⁸F) and the like.

Compound (I) labeled with or substituted by an isotope can be used, forexample, as a tracer used for Positron Emission Tomography (PET) (PETtracer), and is useful in the field of medical diagnosis and the like.

Compound (I) may be an anhydrate or a hydrate. Compound (I) may be asolvate or a non-solvate. Furthermore, compound (I) may be a deuteratedcompound.

Compound (I) may be a crystal, and both a single crystal and crystalmixtures are encompassed in compound (I). Crystals can be produced bycrystallization according to crystallization methods known per se.

In addition, compound (I) may be a pharmaceutically acceptable cocrystalor cocrystal salt. Here, the cocrystal or cocrystal salt means acrystalline substance consisting of two or more particular substanceswhich are solids at room temperature, each having different physicalproperties (e.g., structure, melting point, heat of melting,hygroscopicity, and stability). The cocrystal and cocrystal salt can beproduced by cocrystallization method known per se.

When compound (I) includes isomers such as optical isomers,stereoisomers, regioisomers, rotational isomers, geometrical isomers,and the like, one of the isomers and mixture are also encompassed incompound (I).

Compound (I) or a prodrug thereof (hereinafter sometimes to be simplyabbreviated as the compound of the present invention) has low toxicity(e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductivetoxicity, cardiotoxicity, carcinogenicity), and can be used as it is orin the form of a pharmaceutical composition (in the presentspecification, sometimes to be abbreviated as “medicament of the presentinvention”) after mixing with a pharmacologically acceptable carrieretc. to mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine,horse, swine, monkey) as an agent for the prophylaxis or treatment ofvarious diseases mentioned below.

As a pharmaceutical acceptable carrier here, common organic or inorganiccarrier substances are used as formulation raw materials. Carriers areadded as vehicles, lubricants, binders and disintegrants in the solidformulations; and as solvents, solubilizing agents, suspending Joagents, isotonization agents, buffering agents, soothing agents etc. inthe liquid formulations. If desired, formulation additives such aspreservatives, antioxidants, colorants, sweeteners, etc. can be used.

Preferable examples of the vehicles are as follows: lactose, sucrose,D-mannitol, D-sorbitol, starch, α-starch, dextrin, crystallinecellulose, low-substituted hydroxypropyl cellulose, sodiumcarboxymethylcellulose, gum Arabic, pullulan, light anhydrous silicicacid, synthetic aluminum silicate, and magnesium metasilicic aluminate.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc, colloidal silica, and the like.

Preferable examples of the binders are as follows: α-starch, sucrose,gelatin, gum Arabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

Preferable examples of the disintegrants are as follows: lactose,sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose,croscarmellose sodium, sodium carboxymethyl starch, light anhydroussilicic acid, and low-substituted hydroxypropylcellulose.

Preferable examples of the solvents are as follows: water for injection,physiological saline, Linger solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseedoil.

Preferable examples of the solubilizing agents are as follows:polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzylbenzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine,sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

Preferable examples of the suspending agent include surfactants such asstearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; polysorbates, and polyoxyethylenehydrogenated castor oil.

Preferable examples of the isotonization agents include sodium chloride,glycerin, D-mannitol, D-sorbitol, and glucose.

Preferable examples of the buffering agent include buffer solutions suchas phosphates, acetates, carbonates, and citrates.

Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include p-hydroxybenzoates,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,and sorbic acid.

Preferable examples of antioxidants include sulfites and ascorbates.

Preferable examples of the colorants include water soluble edible tardyes (e.g., edible dyes such as Food Red No. 2 and No. 3, Food YellowNo. 4 and No. 5, Food Blue No. 1 and 2, etc.); water insoluble lake dyes(e.g., aluminum salts of the aforementioned water soluble edible tardyes), and natural dyes (e.g., β-carotene, chlorophyll, ferric oxidered).

Preferable examples of the sweeteners include sodium saccharin,dipotassium glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the medicament of the present inventioninclude oral preparations such as tablet (including sublingual tablet,orally disintegrating tablet), capsule (including soft capsule,microcapsule), granule, powder, troche, syrup, emulsion, suspension andthe like; and parenteral agents such as injection (e.g., subcutaneousinjection, intravenous injection, intramuscular injection,intraperitoneal injection, drip infusion), external preparation (e.g.,dermal preparation, ointment), suppository (e.g., rectal suppository,vaginal suppository), pellet, nasal preparation, pulmonary preparation(inhalant), eye drop and the like, which can be respectively safelyadministered orally or parenterally.

These preparations may be a release control preparation (e.g.,sustained-release microcapsule) such as an immediate-releasepreparation, a sustained-release preparation and the like.

The medicament of the present invention can be manufactured by thecommon methods in the field of formulation technology, for example,methods listed in the Japanese Pharmacopoeia, and the like.

The content of the compound of the present invention in the medicamentof the present invention varies based on the dosage forms, dosages ofthe compound of the present invention, and the like. For example, it isapproximately about 0.1 to 100 wt %.

The compound of the present invention has a superior LSD1 inhibitoryaction and can be used as a prophylactic or therapeutic agent forvarious diseases in mammals (e.g., human, mouse, rat, rabbit, dog, cat,bovine, horse, swine, monkey). Moreover, since the compound of thepresent invention shows low monoamine oxidase A (MAO-A) and monoamineoxidase B (MAO-B) inhibitory activity and high LSD1 selectivity, itcauses fewer side effects.

In addition, the compound of the present invention is expected to show,after transfer into the brain, suppression of a decrease in histone H3K4methylation and suppression of a decrease in Gad1 mRNA expression, whichare derived from the inhibition of LSD1. As a result, it is also usefulas a medicament based on superior actions such as neuronal function,enhancement of neural plasticity, promotion of neurogenesis, andpromotion of BDNF production.

In addition, the compound of the present invention can, after transferinto the brain, suppress a decrease in histone H3K9 methylation derivedfrom LSD1 inhibition. As a result, it is effective for the treatment ofsome diseases associated with a decrease in the methylation of H3K9.

The compound of the present invention can be used as a prophylactic ortherapeutic agent for cancer. Examples of the cancer include breastcancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer,colorectal cancer, rectal cancer, esophagus cancer, duodenal cancer,tongue cancer, pharyngeal cancer, brain tumor, schwannoma, non-smallcell lung cancer, small cell lung cancer, liver cancer, kidney cancer,bile duct cancer, uterine body cancer, cervical cancer, ovarian cancer,urinary bladder cancer, skin cancer, hemangioma, malignant lymphoma,malignant melanoma, thyroid cancer, bone tumor, angiofibroma,retinoblastoma, penile cancer, childhood solid cancer, Kaposi's sarcoma,AIDS-related Kaposi's sarcoma, tumor of maxillary sinus, fibroushistiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia. Amongthese, the compound can be preferably used for prostate cancer,leukemia, and malignant lymphoma.

It is known that the level of H3K4me2, which is a substrate of LSD1, andmemory improvement are correlated (Nature 2007, Vol. 447, page 175), andthe compound of the present invention having a superior LSD1 inhibitoryaction can also be used as a prophylactic or therapeutic agent forneurodegenerative diseases.

The compound of the present invention can be used as a therapeutic agentfor anemia. Examples of anemia include sickle cell anaemia and betathalassemia.

The compound of the present invention can be used as a prophylactic ortherapeutic agent for central nervous system diseases. It is useful as aprophylactic or therapeutic agent for diseases such as

(1) psychiatric diseases [e.g., depression, major depression, bipolardepression, dysthymic disorder, emotional disorder (seasonal affectivedisorder and the like), recurrent depression, postpartum depression,stress disorder, depression symptom, mania, anxiety, generalized anxietydisorder, anxiety syndrome, mood disorder, panic disorder, phobia,social phobia, social anxiety disorder, obsessive disorder,post-traumatic stress syndrome, post-traumatic stress disorder, Tourettesyndrome, adjustment disorder, bipolar disorder, neurosis, schizophrenia(e.g., positive symptom, negative symptom, cognitive impairment),chronic fatigue syndrome, anxiety neurosis, compulsive neurosis, panicdisorder, anxiety symptom, anxious mental state, emotional abnormality,cyclothymia, nervous erethism, faint, addiction, low sex drive,attention deficit hyperactivity disorder (ADHD), psychotic majordepression, refractory major depression, treatment-resistantdepression],(2) neurodegenerative diseases [e.g., Alzheimer's disease,Alzheimer-type senile dementia, Parkinson's disease, Huntington'sdisease (Huntington chorea), multi-infarct dementia, frontotemporaldementia, frontotemporal dementia with Parkinsonism, progressivesupranuclear palsy, Pick's syndrome, Niemann-Pick syndrome, corticobasaldegeneration, vascular dementia, postencephalitic parkinsonism, dementiawith Lewy body, HIV dementia, amyotrophic lateral sclerosis (ALS), motorneurogenesis disease (MND), Creutzfeldt-Jakob disease or prion disease,cerebral palsy, progressive supranuclear palsy, multiple sclerosis,spinocerebellar degeneration (e.g., dentatorubural pallidoluysianatrophy)],(3) developmental disorders, particularly, diseases with intellectualdisability (e.g., autistic spectrum disorders, Rett syndrome, Down'ssyndrome, Kabuki syndrome, fragile X syndrome, Kleefstra syndrome,neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis),(4) age-related cognition and memory disorders [e.g., age-related memorydisorders, senile dementia],(5) sleep disorders [e.g., intrinsic sleep disorders (e.g.,psychophysiological insomnia and the like), extrinsic sleep disorder,circadian rhythm disorders (e.g., time zone change syndrome (jet lag),shift work sleep disorder, irregular sleep-wake pattern, delayed sleepphase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wakedisorder and the like), parasomnia, sleep disorders associated withinternal medical or psychiatric disorder (e.g., chronic obstructivepulmonary disease, Alzheimer's disease, Parkinson's disease,cerebrovascular dementia, schizophrenia, depression, anxiety neurosis),stress insomnia, insomnia, insomniac neurosis, sleep apnea syndrome],(6) respiratory depression caused by anesthetics, traumatic disease, orneurodegenerative disease and the like,(7) epilepsy (e.g., Dravet syndrome), traumatic brain injury, cerebralapoplexy, neurotic anorexia, eating disorder, anorexia nervosa,hyperorexia, other eating disorder, alcohol dependence, alcohol abuse,alcoholic amnesia, alcohol paranoia, alcohol preference, alcoholwithdrawal, alcoholic insanity, alcohol intoxication, alcoholicjealousy, alcoholic mania, alcohol-dependent psychiatric disorder,alcoholic insanity, drug dependence, drug intoxication, pharmacophilia,pharmacophobia, pharmacomania, drug withdrawal, migraine, stressheadache, catatonic headache, diabetic neuropathy, obesity, diabetes,muscular spasm, Meniere's disease, autonomic ataxia, alopecia, glaucoma,hearing loss, hypertension, cardiac disease, tachycardia, congestivecardiac failure, hyperventilation, bronchial asthma, apnea, suddeninfant death syndrome, inflammatory disease, allergic disease,impotence, climacteric disorder, infertility, cancer, immunodeficiencysyndrome caused by HIV infection, immunodeficiency syndrome caused bystress, cerebrospinal meningitis, acromegaly, incontinence, metabolicsyndrome, osteoporosis, peptic ulcer, irritable bowel syndrome,inflammatory bowel disease, ulcerative colitis, Crohn's disease, stressgastrointestinal disorder, stress vomiting, stress ulcer, diarrhea,constipation, postoperative ileus, and the like.

The compound of the present invention is particularly useful as an agentfor the prophylaxis or treatment of diseases such as schizophrenia,developmental disorders, particularly diseases having intellectualdisability (e.g., autistic spectrum disorders, Rett syndrome, Down'ssyndrome, Kabuki syndrome, fragile X syndrome, Kleefstra syndrome,neurofibromatosis type 1, Noonan syndrome, tuberous sclerosis),neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson'sdisease, spinocerebellar degeneration (e.g., dentatoruburalpallidoluysian atrophy) and Huntington's disease (Huntington chorea)),epilepsy (e.g., Dravet syndrome) or drug dependence, and the like.

Since the compound of the present invention has a superior LSD1inhibitory activity, it is expected to show a superior treatment effectsfor the above-mentioned diseases.

The dosage of the compound of the present invention varies depending onthe administration subjects, administration routes, target diseases,symptoms, and the like. For example, for oral administration to adultpatients with cancer, generally a single dose is about 0.01 to 100 mg/kgbody weight, preferably 0.1 to 50 mg/kg body weight, further preferably0.5 to 20 mg/kg body weight, and this dosage is preferably administered1 to 3 times daily.

The compound of the present invention can be used in combination with amedicament such as chemotherapeutic agent, immunotherapeutic agent,medicament inhibiting actions of cell growth factor and receptor thereof(hereinafter to be abbreviated as a concomitant drug).

By combining the compound of the present invention and a concomitantdrug, a superior effect such as

(1) the dose can be reduced as compared to single administration of thecompound of the present invention or a concomitant drug,

(2) the drug to be combined with the compound of the present inventioncan be selected according to the condition of patients (mild case,severe case and the like),

(3) the period of treatment can be set longer by selecting a concomitantdrug having different action and mechanism from the compound of thepresent invention,

(4) a sustained treatment effect can be designed by selecting aconcomitant drug having different action and mechanism from the compoundof the present invention,

(5) a synergistic effect can be afforded by a combined use of thecompound of the present invention and a concomitant drug, and the like,can be achieved.

Hereinafter the compound of the present invention and a concomitant drugused in combination are referred to as the “combination agent of thepresent invention”.

When using the combination agent of the present invention, theadministration time of the compound of the present invention and theconcomitant drug is not restricted, and the compound of the presentinvention or a pharmaceutical composition thereof and the concomitantdrug or a pharmaceutical composition thereof can be administered to anadministration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the dose clinically used, and can be appropriately selecteddepending on an administration subject, administration route, disease,combination and the like.

The administration mode of the combination agent of the presentinvention is not particularly restricted, and it is sufficient that thecompound of the present invention and the concomitant drug are combinedin administration. Examples of such administration mode include thefollowing methods: (1) administration of a single preparation obtainedby simultaneously processing the compound of the present invention andthe concomitant drug, (2) simultaneous administration of two kinds ofpreparations of the compound of the present invention and theconcomitant drug, which have been separately produced, by the sameadministration route, (3) administration of two kinds of preparations ofthe compound of the present invention and the concomitant drug, whichhave been separately produced, by the same administration route in astaggered manner, (4) simultaneous administration of two kinds ofpreparations of the compound of the present invention and theconcomitant drug, which have been separately produced, by differentadministration routes, (5) administration of two kinds of preparationsof the compound of the present invention and the concomitant drug, whichhave been separately produced, by different administration routes in astaggered manner (e.g., administration in the order of the compound ofthe present invention and the concomitant drug, or in the reverse order)and the like.

The dose of the concomitant drug can be appropriately determined basedon the dose employed in clinical situations. The mixing ratio of thecompound of the present invention and a concomitant drug can beappropriately determined depending on the administration subject,administration route, target disease, symptom, combination and the like.

For example, the content of the compound of the present invention in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 0.01 to about 100 wt %,preferably from about 0.1 to about 50 wt %, further preferably fromabout 0.5 to about 20 wt %, based on the preparation.

The content of the concomitant drug in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to about 100 wt %, preferably from about 0.1 toabout 50 wt %, further preferably from about 0.5 to about 20 wt %, basedon the preparation.

The content of additives such as a carrier and the like in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 1 to about 99.99 wt %,preferably from about 10 to about 90 wt %, based on the preparation.

When the compound of the present invention and a concomitant drug areseparately formulated into preparations, the contents thereof aresimilar to the above.

Examples of the chemotherapeutic agent include alkylating agents (e.g.,nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl,cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfantosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan,dacarbazine, ranimustine, estramustine phosphate sodium,triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman,etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin,altretamine, ambamustine, dibrospidium hydrochloride, fotemustine,prednimustine, pumitepa, ribomustin, temozolomide, treosulphan,trophosphamide, zinostatin stimalamer, adozelesin, cystemustine,bizelesin), metabolic antagonists (e.g., mercaptopurine,6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed,enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride,5-FU drug (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur,gallocitabine, emitefur, capecitabine), aminopterin, nelzarabine,leucovorin calcium, tabloid, butocine, folinate calcium, levofolinatecalcium, cladribine, emitefur, fludarabine, gemcitabine,hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone,tiazofurin, ambamustine, bendamustine), antitumor antibiotics (e.g.,actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycinhydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicinhydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride,pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin,mithramycin, sarkomycin, carzinophilin, mitotane, zorubicinhydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride),and plant-derived antitumor agents (e.g., etoposide, etoposidephosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate,teniposide, paclitaxel, docetaxel, vinorelbine).

Examples of the immunotherapeutic agent include picibanil, krestin,schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophagecolony stimulating factor, granulocyte colony stimulating factor,erythropoietin, lymphotoxin, BCG vaccine, corynebacterium parvum,levamisole, polysaccharide K, procodazole and anti-CTLA4 antibody.

Examples of the “medicament inhibiting actions of cell growth factor andreceptor thereof” include anti-VEGF antibody (e.g., Bevacizumab),anti-HER2 antibody (e.g., Trastuzumab, Pertuzumab), anti-EGFR antibody(e.g., Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-VEGFRantibody, anti-HGF antibody, Imatinib mesylate, Erlotinib, Gefitinib,Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib,4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline(AZD-2171), Lestaurtinib, Pazopanib, Canertinib, Tandutinib,3-(4-bromo-2,6-difluorobenzyloxy)-5-[3-[4-(1-pyrrolidinyl)butyl]ureido]isothiazole-4-carboxamide(CP-547632), Axitinib,N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide(AMG-706), Nilotinib,6-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin,N-[4-[4-(4-methylpiperazin-1-yl)-6-(3-methyl-1H-pyrazol-5-ylamino)pyrimidin-2-ylsulfanyl]phenyl]cyclopropanecarboxamide(VX-680),2-[N-[3-[4-[5-[N-(3-fluorophenyl)carbamoylmethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino]ethylphosphate (AZD-1152),4-[9-chloro-7-(2,6-difluorophenyl)-5H-primido[5,4-d][2]benzazepin-2-ylamino]benzoic acid (MLN-8054),N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycinesodium salt (ON-1910Na),4-[8-cyclopentyl-7(R)-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide(BI-2536),5-(4-bromo-2-chlorophenylamino)-4-fluoro-1-methyl-1H-benzimidazole-6-carbohydroxamicacid 2-hydroxyethyl ester (AZD-6244), N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide(PD-0325901) and everolimus (RAD001)

Examples of the concomitant drug for the central nervous system diseasesinclude the following.

benzodiazepine (chlordiazepoxide, diazepam, potassium clorazepate,lorazepam, clonazepam, alprazolam etc.), L-type calcium channelinhibitor (pregabalin etc.), tricyclic or tetracyclic antidepressant(imipramine hydrochloride, amitriptyline hydrochloride, desipraminehydrochloride, clomipramine hydrochloride etc.), selective serotoninreuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride,citalopram hydrobromide, sertraline hydrochloride, paroxetinehydrochloride, escitalopram oxalate etc.), serotonin-noradrenalinereuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride,desvenlafaxine hydrochloride etc.), noradrenaline reuptake inhibitor(reboxetine mesylate etc.), mirtazapine, trazodone hydrochloride,nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate,5-HT1A agonist, (buspirone hydrochloride, tandospirone citrate,osemozotan hydrocloride etc.), 5-HT₃ antagonist (cyamemazine etc.),non-cardioselective β blocker (propranolol hydrochloride, oxprenololhydrochloride etc.), histamine H₁ antagonist (hydroxyzine hydrochlorideetc.), therapeutic drug for schizophrenia (chlorpromazine, haloperidol,sulpiride, clozapine, trifluoperazine hydrochloride, fluphenazinehydrochloride, olanzapine, quetiapine fumarate, risperidone,aripiprazole etc.), CRF antagonist, other antianxiety drug (meprobamateetc.), tachykinin antagonist (MK-869, saredutant etc.), medicament thatacts on metabotropic glutamate receptor, CCK antagonist, β3 adrenalineantagonist (amibegron hydrochloride etc.), GAT-1 inhibitor (tiagabinehydrochloride etc.), N-type calcium channel inhibitor, carbonicanhydrase II inhibitor, NMDA glycine site agonist, NMDA antagonist(memantine etc.), peripheral benzodiazepine receptor agonist,vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1aantagonist, phosphodiesterase inhibitor, opioid antagonist, opioidagonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3,T4), TSH, TRH (Hirtonin, Ceredist), MAO inhibitor (phenelzine sulfate,tranylcypromine sulfate, moclobemide etc.), 5-HT_(2A) antagonist,5-HT_(2A) inverse agonist, COMT inhibitor (entacapone etc.), therapeuticdrug for bipolar disorder (lithium carbonate, sodium valproate,lamotrigine, riluzole, felbamate etc.), cannabinoid CB1 antagonist(rimonabant etc.), FAAH inhibitor, sodium channel inhibitor, anti-ADHDdrug (methylphenidate hydrochloride, methamphetamine hydrochlorideetc.), therapeutic drug for alcohol dependence, therapeutic drug forautism, therapeutic drug for chronic fatigue syndrome, therapeutic drugfor spasm, therapeutic drug for fibromyalgia syndrome, therapeutic drugfor headache, therapeutic drug for insomnia (etizolam, zopiclone,triazolam, zolpidem, ramelteon, indiplon etc.), therapeutic drug forquitting smoking, therapeutic drug for myasthenia gravis, therapeuticdrug for cerebral infarction, therapeutic drug for mania, therapeuticdrug for hypersomnia, therapeutic drug for pain, therapeutic drug fordysthymia, therapeutic drug for autonomic ataxia, therapeutic drug formale and female sexual dysfunction, therapeutic drug for migraine,therapeutic drug for pathological gambler, therapeutic drug for restlesslegs syndrome, therapeutic drug for substance dependence (vareniclineetc.), therapeutic drug for alcohol-related syndrome, therapeutic drugfor irritable bowel syndrome, therapeutic drug for Alzheimer's disease(donepezil, galanthamine, memantine etc.), therapeutic drug forParkinson's disease, therapeutic drug for Huntington's disease(Huntington chorea), therapeutic drug for ALS (riluzole etc.,neurotrophic factor etc.), antiepileptic drug (phenobarbital, phenytoin,valproic acid, clonazepam, topiramate, gabapentin, phenobarbitalethosuximide etc.), therapeutic drug for lipid abnormality such ascholesterol-lowering drug (statin series (pravastatin sodium,atrovastatin, simvastatin, rosuvastatin etc.), fibrate (clofibrateetc.), squalene synthetase inhibitor), therapeutic drug for abnormalbehavior or suppressant of dromomania due to dementia (sedatives,antianxiety drug etc.), apoptosis inhibitor, antiobesity drug,therapeutic drug for diabetes, therapeutic drug for hypertension,therapeutic drug for hypotension, therapeutic drug for rheumatism(DMARD), anti-cancer agent, therapeutic drug for parathyroid (PTH),calcium receptor antagonist, sex hormone or a derivative thereof(progesterone, estradiol, estradiol benzoate etc.), neuronaldifferentiation promoter, nerve regeneration promoter, non-steroidalanti-inflammatory drug (meloxicam, tenoxicam, indomethacin, ibuprofen,celecoxib, rofecoxib, aspirin, indomethacin etc.), steroid(dexamethasone, cortisone acetate etc.), anti-cytokine drug (TNFinhibitor, MAP kinase inhibitor etc.), antibody medicament, nucleic acidor nucleic acid derivative, aptamer drug, and the like.

The above-mentioned concomitant drug may be used in a combination of twoor more kinds at an appropriate ratio.

When the compound of the present invention is used in combination with aconcomitant drug, the respective dosages can be reduced within a saferange in consideration of the opposite effects of the respective drugs.As a result, the opposite effect caused by these agents can be preventedsafely.

The compound of the present invention can also be used in combinationwith a non-medication therapy. Specific examples of the non-medicationtherapy include (1) operation; (2) hypertensive chemical therapy usingangiotensin II and the like; (3) gene therapy; (4) hyperthermic therapy;(5) cryotherapy; (6) laser ablation method; (7) radiation therapy; and(8) immunotherapy.

[Production Method]

The production method of the compound of the present invention isexplained below. Those of ordinary skill in the art can produce compound(I) according to the methods shown in each step of the followingproduction methods and Examples, or a method analogous thereto.

The starting materials and reagents used in each step of the followingproduction methods, as well as the obtained compounds may each form asalt. Examples of such salt include those similar to the salts of theaforementioned compounds of the present invention and the like.

When the compound obtained in each step is a free compound, it can beconverted to a desired salt by a method known per se. Conversely, whenthe compound obtained in each step is a salt, it can be converted to afree form or a desired other kind of salt by a method known per se.

While the compounds obtained in each step can be directly used for thenext reaction in the form of a reaction mixture or as a crude product,the compound obtained in each step can be isolated and/or purifiedaccording to a conventional method from the reaction mixture byseparation means such as concentration, crystallization,recrystallization, distillation, solvent extraction, fractionation,chromatography and the like.

When the compound of a starting material or a reagent for each step iscommercially available, the commercially available product can bedirectly used.

In the reaction of each step, while the reaction time varies dependingon the reagents and solvents to be used, unless particularly indicated,it is generally 1 min to 72 hr, preferably 10 min to 8 hr.

In the reaction of each step, while the reaction temperature variesdepending on the reagents and solvents to be used, unless particularlyindicated, it is generally −78° C. to 300° C., preferably −78° C. to150° C.

In the reaction of each step, while the pressure varies depending on thereagents and solvents to be used, unless particularly indicated, it isgenerally 1 atm to 20 atm, preferably 1 atm to 3 atm.

In the reaction of each step, microwave synthesizers such as Initiatormanufactured by Biotage and the like are sometimes used. While thereaction temperature varies depending on the reagents and solvents to beused, unless particularly indicated, it is generally room temperature to300° C., preferably 50° C. to 250° C. While the reaction time variesdepending on the reagents and solvents to be used, unless particularlyindicated, it is generally 1 min to 48 hr, preferably 1 min to 8 hr.

In the reaction of each step, unless particularly indicated, thereagents are used in 0.5 equivalent to 20 equivalents, preferably 0.8equivalent to 5 equivalents, relative to the substrate. When a reagentis used as a catalyst, the reagent is used in 0.001 equivalent to 1equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative tothe substrate. When the reagent is also used as a reaction solvent, thereagent is used in a solvent amount.

In the reaction of each step, unless particularly indicated, thereaction is performed without solvent, or by dissolving or suspending astarting material in a suitable solvent. Specific examples of thesolvent include the solvents described in Examples, and the following.

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol andthe like;

ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;

aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;

saturated hydrocarbons: cyclohexane, hexane and the like;

amides: N,N-dimethylformamide, N-methylpyrrolidone and the like;

hydrocarbon halides: dichloromethane, carbon tetrachloride and the like;

nitriles: acetonitrile and the like;

sulfoxides: dimethyl sulfoxide and the like;

aromatic organic bases: pyridine and the like;

acid anhydrides: acetic anhydride and the like;

organic acids: formic acid, acetic acid, trifluoroacetic acid and thelike;

inorganic acids: hydrochloric acid, sulfuric acid and the like;

esters: ethyl acetate and the like;

ketones: acetone, methyl ethyl ketone and the like; water.

Two or more kinds of the above-mentioned solvents may be mixed and usedat appropriate ratios.

When a base is used in the reaction of each step, for example, the basesshown below or the bases described in the Examples are used.

inorganic bases: sodium hydroxide, magnesium hydroxide, lithiumhydroxide and the like;

basic salts: sodium carbonate, calcium carbonate, sodium hydrogencarbonate and the like;

organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;

metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;

alkali metal hydrides: sodium hydride and the like;

metal amides: sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide and the like;

organic lithiums: n-butyllithium and the like.

When an acid or an acidic catalyst is used in the reaction of each step,for example, the acids or acidic catalysts shown below or thosedescribed in the Examples are used.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and the like;

organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; Lewisacids: boron trifluoride diethyl ether complex, zinc iodide, anhydrousaluminum chloride, anhydrous zinc chloride, anhydrous iron chloride andthe like.

Unless otherwise specified, the reaction of each step is performed by amethod known per se, for example, the methods described in Jikken KagakuKoza (Courses in Experimental Chemistry), 5th Edition, Volumes 13-19(The Chemical Society of Japan ed.); Shin Jikken Kagaku Koza (NewExperimental Chemistry Course), Volumes 14-15 (The Chemical Society ofJapan ed.); Seimitsu Yuki Gosei (Reactions and Syntheses: In the OrganicChemistry Laboratory), Revised 2nd Edition (L. F. Tietze, Th. Eicher,Nankodo Co., Ltd.); Revised Edition Organic Name Reactions; The ReactionMechanism and Essence (Hideo Togo, Kodansha Ltd.); ORGANIC SYNTHESESCollective Volumes I-VII (John Wiley & Sons, Inc.); Modern OrganicSynthesis in the Laboratory A Collection of Standard ExperimentalProcedures (Jie Jack Li, OXFORD UNIVERSITY PRESS); ComprehensiveHeterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier Japan KK);Strategic Applications of Named Reactions in Organic Synthesis(translated by Kiyoshi Tomioka, Kagaku-Dojin Publishing Company, INC);Comprehensive Organic Transformations (VCH Publishers Inc.) 1989 and thelike, or the methods described in the Examples.

In each step, protection or deprotection of functional groups isperformed according to a method known per se, for example, the methodsdescribed in Wiley-Interscience, 2007, “Protective Groups in OrganicSynthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts); Thieme,2004, “Protecting Groups 3rd Ed.” (P. J. Kocienski) and the like, or themethods described in the Examples.

Examples of the protecting group for hydroxyl group of alcohol and thelike and phenolic hydroxyl group include ether-type protecting groupssuch as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether,tetrahydropyranyl ether and the like; carboxylate-type protecting groupssuch as acetate and the like; sulfonate-type protecting groups such asmethanesulfonate and the like; carbonate-type protecting groups such ast-butyl carbonate and the like; and the like.

Examples of the protecting group for carbonyl group of aldehyde includeacetal-type protecting groups such as dimethyl acetal and the like;cyclic acetal-type protecting groups such as cyclic 1,3-dioxane and thelike; and the like.

Examples of the protecting group for carbonyl group of ketone includeketal-type protecting groups such as dimethyl ketal and the like; cyclicketal-type protecting groups such as cyclic 1,3-dioxane and the like;oxime-type protecting groups such as O-methyloxime and the like;hydrazone-type protecting groups such as N,N-dimethylhydrazone and thelike; and the like.

Examples of the protecting group for carboxyl group include ester-typeprotecting groups such as methyl ester and the like; amide-typeprotecting groups such as N,N-dimethylamide and the like; and the like.

Examples of the protecting group for thiol include ether-type protectinggroups such as benzyl thioether and the like; ester-type protectinggroups such as thioacetate, thiocarbonate, thiocarbamate and the like;and the like.

Examples of the protecting group for amino group, and aromaticheterocycle such as imidazole, pyrrole, indole and the like includecarbamate-type protecting groups such as benzyl carbamate, tert-butylcarbamate and the like; amide-type protecting groups such as acetamideand the like; alkylamine-type protecting groups such asN-triphenylmethylamine and the like; sulfonamide-type protecting groupssuch as methanesulfonamide and the like; and the like.

Protecting groups can be removed by a method known per se, for example,methods using acid, base, ultraviolet rays, hydrazine, phenylhydrazine,sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladiumacetate, trialkylsilyl halide (e.g., trimethylsilyl iodide,trimethylsilyl bromide), reduction methods and the like.

When a reduction reaction is performed in each step, the reducing agentto be used includes metal hydrides such as lithium aluminum hydride,sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane-tetrahydrofuran complex and the like; Raney-nickel; Raney-cobalt;hydrogen; formic acid and the like. When a carbon-carbon double bond ortriple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar catalyst and the like can be used.

When oxidation reaction is performed in each step, the oxidizing agentto be used includes peracids such as m-chloroperbenzoic acid (MCPBA),hydrogen peroxide, t-butyl hydroperoxide and the like; perchlorates suchas tetrabutylammonium perchlorate and the like; chlorates such as sodiumchlorate and the like; chlorites such as sodium chlorite and the like;periodic acids such as sodium periodate and the like; hypervalent iodinereagents such as iodosylbenzene and the like; reagents having manganesesuch as manganese dioxide, potassium permanganate and the like; leadcompounds such as lead tetraacetate and the like; reagents having chromesuch as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC),Jones reagent and the like; halogen compounds such as N-bromosuccinimide(NBS) and the like; oxygen; ozone; sulfur trioxide-pyridine complex;osmium tetroxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When radical cyclization reaction is performed in each step, the radicalinitiator to be used includes azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4,4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. The radical reaction reagent to be used includestributylstannane, tris(trimethylsilyl)silane,1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and thelike.

When the Wittig reaction is performed in each step, the Wittig reagentto be used includes alkylidene phosphoranes and the like. Alkylidenephosphoranes can be prepared by a method known per se, for example, byreacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is performed in each step, the reagentto be used includes phosphonoacetates such as methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate, tert-butyldiethylphosphonoacetate and the like; bases such as alkali metalhydrides, organic lithiums, 1,8-diazabicyclo[5.4.0]undec-7-ene and thelike; lithium chloride, sodium iodide and the like.

When the Friedel-Crafts reaction is performed in each step, the reagentto be used includes Lewis acid and acid chloride or alkylating agents(e.g., alkyl halides, alcohol, olefins and the like). Alternatively,organic acid and inorganic acid can also be used instead of Lewis acid,and acid anhydrides such as acetic anhydride and the like can also beused instead of acid chloride.

When an aromatic nucleophilic substitution reaction is performed in eachstep, nucleophilic agents (e.g., amines, imidazole and the like) andbases (e.g., basic salts, organic bases and the like) are used as thereagents.

When a nucleophilic addition reaction by a nucleophilic agent, anucleophilic addition reaction by carbanion, a nucleophilic 1,4-additionreaction by carbanion (Michael addition) or a nucleophilic substitutionreaction by carbanion is performed in each step, a base used to generatecarbanion includes organic lithiums, metal alkoxides, inorganic bases,organic bases and the like.

When the Grignard reaction is performed in each step, the Grignardreagent includes arylmagnesium halides such as phenylmagnesium bromideand the like; alkylmagnesium halides such as methylmagnesium bromide andthe like. Grignard reagents can be prepared by a method known per se,for example, by reacting alkyl halide or aryl halide with metalmagnesium in ether or tetrahydrofuran as a solvent.

When the Knoevenagel condensation is performed in each step, activemethylene compounds (e.g., malonic acid, diethyl malonate, malononitrileand the like) and bases (e.g., organic bases, metal alkoxides, inorganicbases) sandwiched between two electron withdrawing groups are used asthe reagents.

When the Vilsmeier-Haack reaction is performed in each step, phosphorylchloride and amide derivative (e.g., N,N-dimethylformamide and the like)are used as the reagents.

When an azidation reaction of alcohols, alkyl halides or sulfonates isperformed in each step, the azidating agent to be used includesdiphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide andthe like. For example, when alcohols are azidated, a method usingdiphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), amethod using trimethylsilyl azide and Lewis acid, and the like can beused.

When a reductive amination reaction is performed in each step, thereducing agent to be used includes sodium triacetoxyborohydride, sodiumcyanoborohydride, hydrogen, formic acid, sodium borohydride,2-picoline-borane complex and the like. When the substrate is an aminecompound, a carbonyl compound to be used includes paraformaldehyde,aldehydes such as acetaldehyde and the like, and ketones such ascyclohexanone and the like. When the substrate is a carbonyl compound,amines to be used includes primary amines such as ammonia, methylamineand the like; secondary amines such as dimethylamine and the like, andthe like. An additive such as trimethyl orthoformate and the like may beadded to the reaction.

When the Mitsunobu reaction is performed in each step, azodicarboxylates(e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate(DIAD) and the like) and triphenylphosphine are used as the reagents.

When an esterification reaction, an amidation reaction or a ureationreaction is performed in each step, the reagent to be used includes acylhalides such as acid chloride, acid bromide and the like; and activatedcarboxylic acids such as acid anhydride, active ester form, sulfuricacid ester form and the like. An activator of carboxylic acid includescarbodiimide-type condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine-type condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; carbonate-type condensingagents such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformates such as ethyl chloroformate and thelike; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; or combinations of these andthe like. When a carbodiimide-type condensing agent is used, an additivesuch as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like may be further added to thereaction.

When a coupling reaction is performed in each step, the metal catalystto be used includes palladium compounds such as palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like; nickel compounds such astetrakis(triphenylphosphine)nickel(0) and the like; rhodium compoundssuch as tris(triphenylphosphine)rhodium(III) chloride and the like;cobalt compound; copper compounds such as copper oxide, copper(I) iodideand the like; platinum compound and the like. Furthermore, a base may beadded to the reaction, and examples of such base include inorganicbases, basic salts and the like.

When a thiocarbonylation reaction is performed in each step,diphosphorus pentasulfide is typically used as a thiocarbonylatingagent. However, a reagent having a1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson's reagent) and the like may be used besides diphosphoruspentasulfide.

When the Wohl-Ziegler reaction is performed in each step, thehalogenating agent to be used includes N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. Furthermore, the reaction can be accelerated byadding a radical initiator such as heat, light, benzoyl peroxide,azobisisobutyronitrile and the like to the reaction.

When halogenation of hydroxy group is performed in each step, thehalogenating agent to be used includes hydrohalic acid and acid halideof inorganic acid, specifically, hydrochloric acid, thionyl chloride,phosphorus oxychloride and the like for chlorination, and 48%hydrobromic acid and the like for bromination. In addition, a method forobtaining alkyl halide from alcohol by a reaction of triphenylphosphineand carbon tetrachloride or carbon tetrabromide and the like may beused. Alternatively, a method for synthesizing alkyl halide by atwo-step reaction including converting alcohol to sulfonate and reactingsame with lithium bromide, lithium chloride or sodium iodide may beused.

When the Arbuzov reaction is performed in each step, the reagent to beused includes alkyl halides such as ethyl bromoacetate and the like; andphosphites such as triethyl phosphite, tri(isopropyl)phosphite and thelike.

When a sulfonylation reaction is performed in each step, thesulfonylating agent to be used includes methanesulfonyl chloride,p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonicanhydride and the like.

When hydrolysis is performed in each step, an acid or a base is used asa reagent. When acid hydrolysis of t-butyl ester is performed, formicacid, triethylsilane and the like are sometimes added to reductivelytrap the by-produced t-butyl cation.

When a dehydration reaction is performed in each step, the dehydratingagent to be used includes sulfuric acid, phosphorus pentoxide,phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide, alumina,polyphosphoric acid and the like.

When the Corey-Chaykovsky cyclopropanation reaction is performed in eachstep, the reagent to be used includes trimethylsulfoxonium iodide,potassium tert-butoxide, sodium hydride and the like.

When a carbon monoxide insertion reaction and a subsequent nucleophilicsubstitution reaction by alcohol are performed in each step, the metalcatalyst to be used includes palladium compounds such as palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like; and examples of the phosphine ligandinclude triphenylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl,1,1′-bis(diphenylphosphino)ferrocene, tri-tert-butylphosphine,tricyclohexylphosphine,(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) and the like.

Examples of the alcohol include methanol, ethanol, 2-propanol, benzylalcohol and the like.

This reaction is performed using, as necessary, a phosphine ligandgenerally under a carbon monoxide atmosphere from normal pressure toabout 10 atm in an inert solvent.

When the Curtius rearrangement reaction is performed in each step, thereagents to be used includes diphenylphosphoryl azide and tert-butylalcohol and the like. As reagents, ethyl chloroformate, a base, sodiumazide, tert-butyl alcohol and the like can also be used.

When a diastereomeric salt resolution method is performed in each step,the optically active organic base to be used includes, for example,((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methanamine,(R)-2-amino-3-phenylpropan-1-ol and the like.

The compound obtained in each step may be used after optical resolutionby a known means such as chiral column chromatography, opticalfractional crystallization, diastereomer derivatization and the like.

In the schemes, R⁵ and R⁶ are alkyl groups such as methyl group, ethylgroup, tert-butyl group and the like, and other symbols are each asdefined above. Compound (Ia) to compound (Ik), compound (Iaa) andcompound (Iga) are included in the aforementioned compound (I), and eachof them shows a compound group of compound (I) wherein R³═H. Thethiophene ring, pyrazole ring, naphthalene ring, dihydrobenzofuran ring,pyridine ring and thiazole ring each optionally has substituent(s) onthe ring.

<Reaction Scheme 1>

Compound (Ia) can be produced from compound (1) by the following method.

<Reaction Scheme 2>

Compound (Ib) can be produced from compound (10) by the followingmethod.

Compound (11) can be produced by reacting compound (10) withN-phenylbis(trifluoromethanesulfonimide) and a base. Examples of thebase include sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, cesium carbonate, tripotassium phosphate, sodiummethoxide, sodium ethoxide, triethylamine, diisopropylethylamine,pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like.

Compound (12) can be produced by reacting compound (11) with acrylates.This reaction is performed using a base and a palladium catalyst and,where necessary, a phosphine ligand may also be used. The acrylate to beused includes tert-butyl acrylate, methyl acrylate, ethyl acrylate andthe like. The palladium catalyst to be used includes palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like. Examples of the phosphine ligandinclude triphenylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-, 1′-biphenyl,2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl,1,1′-bis(diphenylphosphino)ferrocene, tri-tert-butylphosphine,tricyclohexylphosphine,(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine),tri(o-tolyl)phosphine and the like. Examples of the base include sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,cesium carbonate, tripotassium phosphate, sodium methoxide, sodiumethoxide, triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene and the like. In this step, forexample, a microwave synthesizer such as Initiator manufactured byBiotage and the like may also be used.

<Reaction Scheme 3>

Compound (Ic) can be produced from compound (19) by the followingmethod.

<Reaction Scheme 4>

Compound (Id) can be produced from compound (31) by the followingmethod.

Compound (32) can be produced by reacting compound (31) with acrylates.This reaction is performed using a base and a palladium catalyst, asnecessary, and a phosphine ligand may also be used. The acrylate to beused includes tert-butyl acrylate, methyl acrylate, ethyl acrylate andthe like. The palladium catalyst to be used includes palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like. Examples of the phosphine ligandinclude triphenylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,2-(dicyclohexylphosphino)-2′,6′-dimethoxy-, 1′-biphenyl,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl,1,1′-bis(diphenylphosphino)ferrocene, tri-tert-butylphosphine,tricyclohexylphosphine,(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine),tri(o-tolyl)phosphine and the like. Examples of the base include sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,cesium carbonate, tripotassium phosphate, sodium methoxide, sodiumethoxide, triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene and the like. In this step, forexample, a microwave synthesizer such as Initiator manufactured byBiotage and the like may also be used.

<Reaction Scheme 5>

Compound (Ie) can be produced from compound (40) by the followingmethod.

<Reaction Scheme 6>

Compound (If) can be produced from compound (49) by the followingmethod.

<Reaction Scheme 7>

Compound (Ig) can be produced from compound (58) by the followingmethod.

<Reaction Scheme 8>

Compound (Ih) can be produced from compound (71) by the followingmethod.

<Reaction Scheme 9>

Compound (Ii) can be produced from compound (81) by the followingmethod.

<Reaction Scheme 10>

Compound (Ij) can be produced from compound (70) by the followingmethod.

<Reaction Scheme 11>

Compound (Ik) can be produced from compound (89) by the followingmethod.

<Reaction Scheme 12>

Compound (Iaa) can be produced from compound (6) or compound (4) by thefollowing method.

<Reaction Scheme 13>

Compound (Iga) can be produced from compound (61) or compound (63) bythe following method.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples.However, the examples do not limit the present invention and the presentinvention can be modified within the scope of the present invention.

The “room temperature” in the following Examples is generally about 10°C. to about 35° C. The ratio for a mixed solvent is, unless otherwisespecified, a volume mixing ratio and % means wt % unless otherwisespecified.

In silica gel column chromatography, the indication of NH means use ofaminopropylsilane-bonded silica gel. In HPLC (high performance liquidchromatography), the indication of C18 means use of octadecyl-bondedsilica gel. Unless otherwise specified, the ratio of elution solvents isa volume mixing ratio.

In the following Examples, the following abbreviations are used.

mp: melting point

MS: mass spectrum

[M+H]⁺, [M−H]⁻: molecular ion peak

M: molar concentration

N: normality

CDCl₃: deuterated chloroform

DMSO-d₆: deuterated dimethyl sulfoxide

¹H NMR: proton nuclear magnetic resonance

LC/MS: liquid chromatography mass spectrometer

ESI: ElectroSpray Ionization

APCI: Atmospheric Pressure Chemical Ionization

THF: tetrahydrofuran

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

TFA: trifluoroacetic acid

SFC: supercritical fluid chromatography

TEA: triethylamine

AA: acetic acid

DMAP: 4-dimethylaminopyridine

¹H NMR was measured by Fourier-transform NMR. For the analyses,ACD/SpecManager (trade name) and the like were used. A peak showing verymild proton of hydroxyl group, amino group or the like is not described.

MS was measured by LC/MS. As the ionization method, ESI method or APCImethod was used. The data indicates measured values (found). Generally,a molecular ion peak is observed. However, when a compound has atert-butoxycarbonyl group, a peak free of a tert-butoxycarbonyl group ortert-butyl group may be observed as a fragment ion. When a compound hasa hydroxyl group, a peak free of H₂O may be observed as a fragment ion.In the case of a salt, a molecular ion peak or a fragment ion peak of afree form is generally observed.

The unit of the sample concentration (c) in optical rotation ([α]_(D))is g/100 mL.

As the elemental analytical values (Anal.), Calculated (Calcd) andmeasured values (Found) are described.

Example 14-(trans-2-aminocyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride A) (E)-ethyl 3-(5-bromo-2-methylthiophene-3-yl)acrylate

To a mixture of potassium tert-butoxide (4.59 g) and dry THF (60 mL) wasadded ethyl diethylphosphonoacetate (7.5 mL) at −5° C., and the mixturewas stirred for 20 min. To the reaction mixture was added a mixture of5-bromo-2-methylthiophene-3-carbaldehyde (7.0 g) and dry THF (10 mL) at−5° C., and the mixture was stirred for 30 min. To the reaction mixturewas added water (100 mL), and the mixture was extracted twice with ethylacetate (100 mL each). The extracts were combined, dried over anhydroussodium sulfate, and concentrated under reduced pressure to give thetitle compound (7.2 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.17-1.35 (3H, m), 2.45 (3H, s), 4.19 (2H,q, J=5.8 Hz), 6.40 (1H, d, J=15.7 Hz), 7.48 (1H, d, J=15.7 Hz), 7.78(1H, s).

B) ethyl trans-2-(5-bromo-2-methylthiophen-3-yl)cyclopropanecarboxylate

To a suspension of sodium hydride (50% in oil, 2.26 g) in DMSO (50 mL)was added trimethylsulfoxonium iodide (10.4 g), and the mixture wasstirred at room temperature for 1 hr. To the reaction mixture was addeda mixture of ethyl (E)-ethyl 3-(5-bromo-2-methylthiophen-3-yl)acrylate(6.5 g) and DMSO (30 mL), and the mixture was stirred at roomtemperature for 4 hr. To the reaction mixture was added ice water (200mL), and the mixture was extracted with ethyl acetate (100 mL, twice).The extracts were combined, washed with saturated brine (100 mL), driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (3.5 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.23 (3H, t, J=5.2 Hz), 1.24-1.29 (1H, m),1.30-1.40 (1H, m), 1.86-1.90 (1H, m), 2.23-2.28 (1H, m), 2.33 (3H, s),4.09 (2H, q, J=7.1 Hz), 6.82 (1H, s).

C) trans-2-(5-bromo-2-methylthiophen-3-yl)cyclopropanecarboxylic acid

Ethyl trans-2-(5-bromo-2-methylthiophen-3-yl)cyclopropanecarboxylate(500 mg) was dissolved in methanol (8 mL), a mixture of sodium hydroxide(138 mg) and water (2 mL) was added at 0° C., and the mixture wasstirred at room temperature for 2 hr. The reaction mixture wasconcentrated under reduced pressure, and adjusted to pH 6 with 2 mol/Lhydrochloric acid at an inside temperature of not more than 10° C. Theprecipitated solid was collected by filtration and dried under reducedpressure to give the title compound (350 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.22-1.27 (1H, m), 1.31-1.36 (1H, m),1.72-1.76 (1H, m), 2.19-2.24 (1H, m), 2.34 (3H, s), 6.79 (1H, s), 12.31(1H, brs).

D) tert-butyl(trans-2-(5-bromo-2-methylthiophen-3-yl)cyclopropyl)carbamate

To a mixture oftrans-2-(5-bromo-2-methylthiophen-3-yl)cyclopropanecarboxylic acid (1.5g) and tert-butyl alcohol (70 mL) were added triethylamine (8.3 mL) anddiphenylphosphoryl azide (3.7 mL) at room temperature, and the mixturewas stirred at 90° C. for 16 hr. The reaction mixture was cooled to roomtemperature, and concentrated under reduced pressure. To the residue wasadded water (100 mL), and the mixture was extracted twice with ethylacetate (200 mL each). The extracts were combined, washed with saturatedbrine (100 mL), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (0.75g).

¹H NMR (400 MHz, DMSO-d₆) δ 0.99-1.05 (2H, m), 1.38 (9H, s), 1.72-1.76(1H, m), 2.35 (3H, s), 2.52-2.54 (1H, m), 6.72 (1H, s), 7.20 (1H, s).

E) methyl4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate

A mixture of tert-butyl(trans-2-(5-bromo-2-methylthiophen-3-yl)cyclopropyl)carbamate (1.3 g),diisopropylethylamine (3.42 mL),dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (0.96 g) andmethanol (45 mL) was heated under a carbon monoxide atmosphere (10 atm)at 80° C. for 16 hr. After cooling to room temperature, the insolublematerial was filtered off, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (0.90g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.05-1.15 (2H, m), 1.36 (9H, s), 1.73-1.78(1H, m), 2.47 (3H, s), 2.50-2.55 (1H, m), 3.76 (3H, s), 7.25 (1H, brs),7.34 (1H, s)

F)4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid

Methyl4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate(900 mg) was dissolved in methanol (45 mL), a mixture of sodiumhydroxide (1160 mg) and water (15 mL) was added at 0° C., and themixture was stirred at room temperature for 16 hr. The reaction mixturewas concentrated under reduced pressure, and water (10 mL) was added tothe residue. The mixture was adjusted to pH 6 with 2 mol/L hydrochloricacid at an inside temperature of not more than 10° C., and extractedwith 20% methanol-dichloromethane solution (100 mL each). The extractswere combined, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give the title compound (660 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.02-1.07 (2H, m), 1.38 (9H, s), 1.72-1.76(1H, m), 2.45 (3H, s), 2.49-2.54 (1H, m), 7.24 (2H, s), 12.79 (1H, s).

G) tert-butyl(trans-2-(2-methyl-5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate

4-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid (100 mg), 5-methyl-1,3,4-thiadiazol-2-amine (44.8 mg) andtriethylamine (0.187 mL) were dissolved in DMF (3.0 mL), and the mixturewas cooled to 0° C.O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (153 mg) was added, and the mixture was stirred atroom temperature overnight. The reaction mixture was poured into water,and the mixture was extracted with ethyl acetate. The extract wassuccessively washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate) andconcentrated under reduced pressure. The obtained residue was dilutedwith ethyl acetate-THF, successively washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give the title compound (64 mg).

MS: [M+H]⁺ 395.2.

H)4-(trans-2-aminocyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride

To a mixture of tert-butyl(trans-2-(2-methyl-5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate(64 mg), ethyl acetate (5 mL) and methanol (2 mL) was added 4 mol/Lhydrogen chloride/ethyl acetate solution (0.811 mL) at room temperature,and the mixture was stirred at room temperature for 3 days. Theprecipitated solid was collected by filtration and dried under reducedpressure to give the title compound (45 mg).

Example 24-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride

To a mixture of4-(trans-2-aminocyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride (42 mg), sodium hydrogen carbonate (38.4 mg), THF (0.5mL) and methanol (0.5 mL) was added cyclopropanecarbaldehyde (13 μL) atroom temperature. Under a nitrogen atmosphere, the reaction mixture wasstirred at 50° C. for 1.5 hr and at room temperature for 1 hr. To thereaction mixture was added cyclopropanecarbaldehyde (8.8 μL) at roomtemperature, and the mixture was stirred at 50° C. for 1.5 hr under anitrogen atmosphere and at room temperature for 30 min. Sodiumborohydride (8.7 mg) was added under ice-cooling and the reactionmixture was stirred for 30 min under a nitrogen atmosphere. Underice-cooling, to the reaction mixture were added ethyl acetate (5 mL),water and saturated aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and the aqueous layer was extracted with a mixture ofethyl acetate and THF. The combined organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was washed with a mixture of ethyl acetate anddiisopropyl ether, and dissolved in methanol. A 2 mol/L hydrogenchloride/methanol solution (2 mL) was added, and the mixture wasconcentrated under reduced pressure. The residue was crystallized fromethanol/diisopropyl ether to give the title compound (25.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.33-0.43 (2H, m), 0.55-0.65 (2H, m),1.06-1.14 (1H, m), 1.16-1.27 (1H, m), 1.53-1.62 (1H, m), 2.40-2.47 (1H,m), 2.52 (3H, s), 2.62 (3H, s), 2.85-3.02 (3H, m), 7.85 (1H, brs), 9.24(2H, brs), 12.66 (1H, brs).

Example 35-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-1-methyl-1H-pyrazole-3-carboxamidehydrochloride A) methyl1-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate

To a mixture of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate(2.404 g), diisopropylethylamine (5.38 mL) and DMF (24 mL) was addedN-phenylbis(trifluoromethanesulfonimide) (6.05 g) at 0° C., and themixture was stirred at room temperature overnight under a nitrogenatmosphere. The reaction mixture was poured into water, extracted withethyl acetate, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/ethyl acetate)and concentrated under reduced pressure to give the title compound (3.92g).

¹H NMR (300 MHz, CDCl₃) δ 3.92 (3H, s), 3.94 (3H, s), 6.69 (1H, s).

B) methyl5-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)-1-methyl-1H-pyrazole-3-carboxylate

A mixture of methyl1-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate(890 mg), tert-butyl acrylate (1.35 mL), tri(o-tolyl)phosphine (188 mg),palladium acetate (69.3 mg), triethylamine (1.29 mL) and DMF (8 mL) wasstirred at 80° C. for 3 hr under a nitrogen atmosphere. The reactionmixture was poured into water at room temperature, and the mixture wasextracted with ethyl acetate, washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane/ethyl acetate) and concentrated under reduced pressure to givethe title compound (144 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.53 (9H, s), 3.93 (3H, s), 4.02 (3H, s), 6.34(1H, d, J=15.9 Hz), 7.07 (1H, s), 7.45 (1H, d, J=15.9 Hz).

C) methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-1-methyl-1H-pyrazole-3-carboxylate

By a method similar to that of Example 1, step B, the title compound wasobtained.

MS: [M+H]⁺ 281.2.

D)2-(3-(methoxycarbonyl)-1-methyl-1H-pyrazol-5-yl)cyclopropanecarboxylicacid

To methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-1-methyl-1H-pyrazole-3-carboxylate(135 mg) was added trifluoroacetic acid (2 mL) at 0° C., and the mixturewas stirred at room temperature for 4 hr and concentrated under reducedpressure. Water was added to the residue, and the mixture was extractedwith ethyl acetate, successively washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The obtained residue was diluted with ethyl acetate andsaturated aqueous sodium hydrogen carbonate solution. The aqueous layerwas separated, acidified with 2 mol/L hydrochloric acid, and extractedwith ethyl acetate. The extract was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was diluted with toluene andconcentrated under reduced pressure to give the title compound (100 mg).

MS: [M+H]⁺ 225.1.

E)5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-1-methyl-1H-pyrazole-3-carboxamidehydrochloride

By a method similar to that of Example 1, steps D, F, G and H andExample 2, the title compound was obtained.

Example 45-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)-1-methyl-1H-pyrazole-3-carboxamidehydrochloride

By a method similar to that of Example 3, steps A, B, C and D andExample 1, steps D, F, G and H, the title compound was obtained.

Example 54-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-naphthamidedihydrochloride A) 3-bromo-N-methoxy-N-methyl-1-naphthamide

3-Bromo-1-naphthoic acid (3.00 g), N,O-dimethylhydroxylaminehydrochloride (1.32 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (2.80 g) and anhydrous 1-hydroxybenzotriazole (1.94 g)were dissolved in anhydrous DMF (60.0 mL), triethylamine (4.16 mL) wasadded, and the mixture was stirred at room temperature for 16 hr. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (2.69g).

MS: [M+H]⁺ 293.9.

B) 3-bromo-1-naphthaldehyde

To a solution of 3-bromo-N-methoxy-N-methyl-1-naphthamide (2.69 g) inTHF (50.0 mL) was slowly added 1.5 mol/L diisobutylaluminum hydridetoluene solution (9.15 mL) at 0° C., and the mixture was stirred at 0°C. for 2 hr under a nitrogen atmosphere. To the reaction mixture wasadded 1 mol/L hydrochloric acid at 0° C., and the mixture was extractedwith ethyl acetate. The extract was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate) to give the title compound(1.52 g).

¹H NMR (300 MHz, CDCl₃) δ 7.57-7.66 (1H, m), 7.67-7.74 (1H, m), 7.84(1H, d, J=8.3 Hz), 8.06 (1H, d, J=2.3 Hz), 8.26 (1H, s), 9.16 (1H, d,J=8.7 Hz), 10.36 (1H, s).

C) (E)-tert-butyl 3-(3-bromonaphthalen-1-yl)acrylate

Lithium chloride (0.28 g) was dried in vacuo, and acetonitrile (20.0 mL)was added. To the mixture were added 3-bromo-1-naphthaldehyde (1.52 g)and tert-butyl diethylphosphonoacetate (1.71 g) at 0° C., and themixture was stirred at 0° C. for 5 min under a nitrogen atmosphere. Tothe reaction mixture was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.02mL) at 0° C., and the mixture was stirred at room temperature for 18 hrunder a nitrogen atmosphere. Water was added to the reaction mixture atroom temperature, and the mixture was extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (1.93 g).

¹H NMR (300 MHz, CDCl₃) δ 1.57 (9H, s), 6.46 (1H, d, J=15.9 Hz),7.51-7.61 (2H, m), 7.75-7.82 (2H, m), 8.02 (1H, d, J=1.5 Hz), 8.10-8.16(1H, m), 8.32 (1H, d, J=15.9 Hz).

D)4-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-naphthamidedihydrochloride

By a method similar to that of Example 1, steps B, D, E, F, G and H andExample 3, step D, the title compound was obtained.

Example 6N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)-2-naphthamidehydrochloride A) tert-butyl(trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)naphthalen-1-yl)cyclopropyl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

4-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-naphthamidedihydrochloride (56.6 mg) and sodium hydrogen carbonate (35.9 mg) weredissolved in THF (5.00 mL)/methanol (5.00 mL), andtetrahydro-2H-pyran-4-carbaldehyde (19.5 mg) was added. Under a nitrogenatmosphere, the reaction mixture was stirred at 60° C. for 3 hr, andsodium borohydride (10.8 mg) was added at 0° C. The reaction mixture wasstirred at room temperature for 2 hr, to the reaction mixture was addeddi-tert-butyl dicarbonate (0.099 mL), and the mixture was stirred atroom temperature for 16 hr. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (33.5 mg).

MS: [M+H]⁺ 523.1.

B)N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)-2-naphthamidehydrochloride

By a method similar to that of Example 1, step H, the title compound wasobtained.

Anal. Calcd for C₂₃H₂₆N₄O₂S HCl: C, 60.19; H, 5.93; N, 12.21. Found: C,59.52; H, 5.87; N, 11.88.

Example 74-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-naphthamidedihydrochloride

By a method similar to that of Example 6, the title compound wasobtained.

Anal. Calcd for C₂₁H₂₂N₄OS 2HCl: C, 55.88; H, 5.36; N, 12.41. Found: C,56.60; H, 5.56; N, 12.39.

Example 8N-(4,4-difluorocyclohexyl)-5-methyl-4-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamidehydrochloride A) tert-butyl(trans-2-(5-((4,4-difluorocyclohexyl)carbamoyl)-2-methylthiophen-3-yl)cyclopropyl)carbamate

4-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid (100 mg), 4,4-difluorocyclohexanamine hydrochloride (63.5 mg) andtriethylamine (0.187 mL) were dissolved in DMF (1.0 mL),0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (153 mg) was added at room temperature, and themixture was stirred overnight. Water was added to the reaction mixture,and the resulting precipitate was collected by filtration to give thetitle compound (140 mg).

MS: [M+H]⁺ 415.3.

B)4-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamidehydrochloride

To a solution (2.0 mL) of tert-butyl(trans-2-(5-((4,4-difluorocyclohexyl)carbamoyl)-2-methylthiophen-3-yl)cyclopropyl)carbamate(140 mg) in ethyl acetate was added 4 mol/L hydrogen chloride/ethylacetate solution (2.0 mL) at room temperature, and the mixture wasstirred at room temperature for 3 days. The resulting precipitate wascollected by filtration to give the title compound (90 mg).

MS: [M-HCl+H]⁺ 315.2.

C)N-(4,4-difluorocyclohexyl)-5-methyl-4-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamidehydrochloride

To a mixture of4-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamidehydrochloride (48.9 mg), sodium hydrogen carbonate (46.8 mg), THF (1 mL)and methanol (1 mL) was added tetrahydro-2H-pyran-4-carbaldehyde (19.1mg) at room temperature. The reaction mixture was stirred at 60° C. for1.5 hr and at room temperature for 30 min, and sodium borohydride (7.91mg) was added at 0° C. Under a nitrogen atmosphere, the reaction mixturewas stirred at room temperature for 1 hr. To the reaction mixture wereadded ethyl acetate, water and saturated aqueous sodium hydrogencarbonate solution under ice-cooling, and the mixture was extracted withethyl acetate. The extract was washed with water and saturated brine.The organic layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (ethyl acetate/methanol).To the obtained fraction was added 4 mol/L hydrogen chloride/ethylacetate solution and the mixture was concentrated under reduced pressureto give the title compound (42.3 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.11-1.34 (3H, m), 1.54-2.12 (13H, m),2.83-3.04 (4H, m), 3.21-3.34 (2H, m), 3.86 (3H, dd, J=11.3, 2.3 Hz),7.40 (1H, s), 8.12 (1H, d, J=7.9 Hz), 8.56 (1H, brs), 9.39 (2H, brs).

Example 97-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1-benzofuran-5-carboxamidedihydrochloride

By a method similar to that of Example 1, the title compound wasobtained.

Example 107-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1-benzofuran-5-carboxamidedihydrochloride

By a method similar to that of Example 2, the title compound wasobtained.

Example 117-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-2,3-dihydro-1-benzofuran-5-carboxamidehydrochloride

By a method similar to that of Example 1, steps G and H and Example 2,the title compound was obtained.

Example 12N-(4,4-difluorocyclohexyl)-7-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)-2,3-dihydro-1-benzofuran-5-carboxamidehydrochloride

By a method similar to that of Example 2, the title compound wasobtained.

Example 135-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)-6-methylnicotinamidedihydrochloride

By a method similar to that of Example 1, the title compound wasobtained.

Example 145-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-6-methylnicotinamidedihydrochloride

By a method similar to that of Example 2, the title compound wasobtained.

Example 153-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-1-naphthamidedihydrochloride A) (E)-methyl3-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-1-naphthoate

A mixture of methyl 3-bromo-1-naphthoate (500 mg), tert-butyl acrylate(0.422 mL), tri(o-tolyl)phosphine (114 mg), palladium acetate (43.2 mg),triethylamine (0.781 mL) and anhydrous DMF (3.00 mL) was heated at 100°C. for 1 hr under microwave irradiation. The reaction mixture was pouredinto water and the mixture was extracted with ethyl acetate. The extractwas washed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/ethyl acetate)and concentrated under reduced pressure to give the title compound (575mg).

¹H NMR (300 MHz, CDCl₃) δ1.56 (9H, s), 4.03 (3H, s), 6.55 (1H, d, J=15.8Hz), 7.52-7.59 (1H, m), 7.60-7.67 (1H, m), 7.74 (1H, d, J=15.8 Hz), 7.89(1H, d, J=7.5 Hz), 8.07 (1H, s), 8.37 (1H, d, J=1.9 Hz), 8.87 (1H, d,J=8.7 Hz).

B)3-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-1-naphthamidedihydrochloride

By a method similar to that of Example 1, steps B, D, F, G and H andExample 3, step D, the title compound was obtained.

Anal. Calcd for C₁₇H₁₆N₄OS 2HCl H₂O: C, 49.16; H, 4.85; N, 13.49. Found:C, 49.12; H, 5.47; N, 13.12.

Example 16N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)-1-naphthamidedihydrochloride

By a method similar to that of Example 6, the title compound wasobtained.

Anal. Calcd for C₂₃H₂₆N₄O₂S, 2HCl 1.4H₂O: C, 53.06; H, 5.96; N, 10.76.Found: C, 52.93; H, 5.96; N, 10.31.

Example 174-(trans-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide1/2 fumarate

To a mixture of4-(trans-2-aminocyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride (45 mg), triethylamine (0.034 mL), trimethylorthoformate (0.027 mL) and methanol (2.0 mL) was added cyclobutanone(0.014 mL) at room temperature, and the mixture was stirred at roomtemperature overnight. Sodium borohydride (9.3 mg) was added underice-cooling, and the reaction mixture was stirred at 0° C. for 10 min.After stirring, water was added under ice-cooling, and the mixture wasextracted with ethyl acetate. The extract was washed with water andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate/methanol) and concentrated under reduced pressure. The obtainedresidue was suspended in ethyl acetate, and a solution of fumaric acid(14.2 mg) in ethanol was added at room temperature. The reaction mixturewas stirred for 30 min, and the resulting precipitate was collected byfiltration to give the title compound (23 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.78-0.88 (1H, m), 0.91-1.02 (1H, m),1.52-1.83 (5H, m), 2.05-2.19 (2H, m), 2.20-2.30 (2H, m), 2.47 (3H, s),2.61 (3H, s), 6.57-6.62 (1H, m), 7.70-7.77 (1H, m).

Example 184-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamidefumarate

By a method similar to that of Example 19, the title compound wassynthesized.

Example 194-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidefumarate A) tert-butyl(trans-2-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate

4-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid (100 mg), tetrahydro-2H-pyran-4-amine (37.4 mg) and triethylamine(0.187 mL) were dissolved in DMF (1.0 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (153 mg) was added at room temperature, and themixture was stirred overnight. The reaction mixture was poured intowater, and the resulting precipitate was collected by filtration to givethe title compound (122 mg).

MS: [M+H]⁺ 381.2.

B)4-(trans-2-aminocyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride

To a mixture of tert-butyl(trans-2-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate(122 mg) and ethyl acetate (2 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (1.60 mL) at room temperature, and themixture was stirred at room temperature overnight. The resultingprecipitate was collected by filtration to give the title compound (95mg).

MS: [M-HCl+H]⁺ 281.2.

C) 4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidefumarate

To a mixture of4-(trans-2-aminocyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride (45 mg), triethylamine (0.040 mL) and methanol (2.0 mL)was added cyclopropanecarbaldehyde (14.9 mg) at room temperature, andthe reaction mixture was stirred at room temperature overnight. Sodiumborohydride (10.8 mg) was added under ice-cooling, and the reactionmixture was stirred at 0° C. for 10 min. After stirring, water was addedunder ice-cooling, and the mixture was extracted with ethyl acetate. Theextract was washed with water and saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (ethyl acetate/methanol) and concentrated underreduced pressure. The obtained residue was suspended in ethyl acetate, asolution of fumaric acid (13.5 mg) in ethanol was added at roomtemperature, and the reaction mixture was stirred for 30 min. Afterstirring, the resulting precipitate was collected by filtration to givethe title compound (40 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.09-0.18 (2H, m), 0.38-0.47 (2H, m),0.82-0.98 (2H, m), 1.02-1.13 (1H, m), 1.41-1.59 (2H, m), 1.66-1.77 (2H,m), 1.79-1.90 (1H, m), 2.36-2.45 (4H, m), 2.57 (2H, dd, J=6.82, 1.89Hz), 3.28-3.42 (2H, m), 3.80-3.96 (3H, m), 6.57 (2H, s), 7.26 (1H, s),8.04 (1H, d, J=7.57 Hz).

Example 205-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamidedihydrochloride

By a method similar to that of Example 2, the title compound wassynthesized.

Example 21N-(4,4-difluorocyclohexyl)-5-methyl-4-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-2-carboxamidefumarate

4-(trans-2-Aminocyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamidehydrochloride (49 mg) and borane-2-methylpyridine complex (44.8 mg) weredissolved in methanol (2.0 mL)/acetic acid (0.20 mL),tetrahydro-4H-pyran-4-one (21.0 mg) was added, and the mixture wasstirred at room temperature overnight. Under ice-cooling, to thereaction mixture was added saturated aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethyl acetate)and concentrated under reduced pressure. The obtained residue wasdissolved in ethyl acetate, a solution of fumaric acid (9.32 mg) inethanol was added at room temperature, and the reaction mixture wasstirred for 30 min. After stirring, the mixture was concentrated underreduced pressure to give the title compound (12 mg).

¹H NMR (300 MHz, METHANOL-d₄) δ 1.04-1.15 (1H, m), 1.21-1.33 (1H, m),1.41-2.16 (14H, m), 2.40 (3H, s), 2.64-2.74 (1H, m), 3.30-3.42 (2H, m),3.77-3.96 (3H, m), 6.58-6.64 (2H, m), 7.14-7.17 (1H, m).

Example 224-(trans-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride

To a mixture of4-(trans-2-aminocyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride (50 mg), triethylamine (0.040 mL), trimethylorthoformate (0.032 mL) and methanol (2.0 mL) was added cyclobutanone(15.1 mg) at room temperature, and the mixture was stirred at roomtemperature overnight. Sodium borohydride (10.8 mg) was added underice-cooling, and the reaction mixture was stirred for 10 min. Water wasadded under ice-cooling, and the mixture was extracted with ethylacetate. The extract was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (ethyl acetate/methanol).To the obtained fraction was added 4 mol/L hydrogen chloride/ethylacetate solution and the reaction mixture was concentrated under reducedpressure. The obtained residue was crystallized from ethanol/heptane togive the title compound (10 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.12-1.22 (1H, m), 1.47-1.58 (1H, m),1.75-1.91 (2H, m), 2.14-2.32 (4H, m), 2.35-2.44 (1H, m), 2.47-2.49 (3H,m), 2.71-2.85 (1H, m), 3.80 (3H, s), 3.82-3.92 (1H, m), 7.47-7.50 (1H,m), 7.50-7.53 (1H, m), 7.89-7.95 (1H, m), 9.47-9.67 (2H, m) 10.25-10.32(1H, m).

Example 235-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride A) ethyl (2E)-3-(4-bromothiophen-2-yl)acrylate

Lithium chloride (453 mg) was dried in high vacuo, and acetonitrile (40mL) was added. To this mixture were added4-bromothiophene-2-carbaldehyde (2.00 g) and ethyldiethylphosphonoacetate (2.46 g) at 0° C., and the mixture was stirredat 0° C. for 5 min under a nitrogen atmosphere. To the reaction mixturewas added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.66 mL) at 0° C., and themixture was stirred at room temperature overnight under a nitrogenatmosphere. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was successively washed withwater and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate) to give the titlecompound (2.52 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.18-1.31 (3H, m), 4.18 (2H, q, J=7.07 Hz),6.37 (1H, d, J=15.90 Hz), 7.58-7.89 (3H, m).

B) ethyl trans-2-(4-bromothiophen-2-yl)cyclopropanecarboxylate

To a suspension of trimethylsulfoxonium iodide (2.54 g) in DMSO (20 mL)was added sodium hydride (60% in oil, 461 mg), and the mixture wasstirred at room temperature for 30 min. To the reaction mixture wasadded a solution of ethyl (2E)-3-(4-bromothiophen-2-yl)acrylate (2.51 g)in DMSO (10 mL), and the mixture was stirred at room temperatureovernight under a nitrogen atmosphere. Water was added to the reactionmixture at 0° C., and the mixture was extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (1.27 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.20 (3H, t, J=7.19 Hz), 1.35-1.54 (2H, m),1.97 (1H, ddd, J=8.42, 5.40, 3.98 Hz), 2.58-2.67 (1H, m), 4.05-4.16 (2H,m), 6.98 (1H, dd, J=1.51, 0.76 Hz), 7.46 (1H, d, J=1.51 Hz).

C) trans-2-(4-bromothiophen-2-yl)cyclopropanecarboxylic acid

Ethyl trans-2-(4-bromothiophen-2-yl)cyclopropanecarboxylate (1.27 g) wasdissolved in THF (5 mL) and ethanol (5 mL), 8 mol/L aqueous sodiumhydroxide solution (1.44 mL) was added at 0° C., and the mixture wasstirred at room temperature overnight. The reaction mixture wasacidified with 1 mol/L hydrochloric acid at 0° C., and extracted withethyl acetate. The extract was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (1.11g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.29-1.50 (2H, m), 1.78-1.87 (1H, m),2.54-2.63 (1H, m), 6.97 (1H, dd, J=1.51, 0.76 Hz), 7.45 (1H, d, J=1.51Hz), 12.49 (1H, brs).

D) tert-butyl (trans-2-(4-bromothiophen-2-yl)cyclopropyl)carbamate

To a mixture of trans-2-(4-bromothiophen-2-yl)cyclopropanecarboxylicacid (1.10 g) and tert-butyl alcohol (10 mL) were added triethylamine(0.745 mL) and diphenylphosphoryl azide (1.15 mL) at room temperature,and the mixture was stirred at room temperature for 2 hr, and then at80° C. overnight. The reaction mixture was cooled to room temperature,water was added, and the mixture was extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (930 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.04-1.23 (2H, m), 1.38 (9H, s), 2.07 (1H,ddd, J=9.09, 6.06, 3.03 Hz), 2.61 (1H, brs), 6.80 (1H, d, J=0.76 Hz),7.22-7.34 (1H, m), 7.38 (1H, d, J=1.51 Hz).

E) methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate

A mixture of tert-butyl(trans-2-(4-bromothiophen-2-yl)cyclopropyl)carbamate (925 mg),triethylamine (0.810 mL),dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (425 mg) andmethanol (100 mL) was stirred at 90° C. for 8 hr under a carbon monoxideatmosphere (3 atm). The insoluble material was filtered off and washedwith methanol, and the filtrate was concentrated under reduced pressure.The residue was extracted with ethyl acetate and water, and the organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (813 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.08-1.23 (2H, m), 1.39 (9H, s), 2.08 (1H,ddd, J=9.18, 6.34, 3.03 Hz), 2.60 (1H, brs), 3.76 (3H, s), 7.08-7.15(1H, m), 7.29 (1H, brs), 8.07 (1H, d, J=1.51 Hz).

F) methyl 5-(trans-2-aminocyclopropyl)thiophene-3-carboxylatehydrochloride

To a mixture of methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(450 mg) and ethyl acetate (5 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (3.78 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved inmethanol, and ethyl acetate was added. The precipitated solid wascollected by filtration and washed with ethyl acetate to give the titlecompound (320 mg)

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (1H, dt, J=7.76, 6.15 Hz), 1.47 (1H,ddd, J=10.13, 5.96, 4.73 Hz), 2.56 (1H, ddd, J=9.75, 6.15, 3.79 Hz),2.81-2.94 (1H, m), 3.73-3.80 (3H, m), 7.23 (1H, d, J=0.76 Hz), 8.12-8.18(1H, m), 8.51 (3H, brs).

G) methyl5-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiophene-3-carboxylate

A mixture of methyl 5-(trans-2-aminocyclopropyl)thiophene-3-carboxylatehydrochloride (50.0 mg), sodium hydrogen carbonate (44.9 mg), THF (2 mL)and methanol (2 mL) was stirred at room temperature for 30 min, andcyclopropanecarbaldehyde (18.0 mg) was added. Under a nitrogenatmosphere, the reaction mixture was stirred at 60° C. for 2 hr, andsodium borohydride (12.1 mg) was added at 0° C. Under a nitrogenatmosphere, the reaction mixture was stirred at room temperature for 1.5hr, and to the reaction mixture were added ethyl acetate and water underice-cooling. The mixture was extracted with ethyl acetate, and theextract was washed with water and saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the obtained residue was dissolved in THF (3 mL).Triethylamine (0.037 mL) and di-tert-butyl dicarbonate (0.077 mL) wereadded, and the reaction mixture was stirred at room temperatureovernight. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (75.7mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.09-0.30 (2H, m), 0.34-0.52 (2H, m),0.91-1.01 (1H, m), 1.20-1.28 (1H, m), 1.28-1.43 (10H, m), 2.23-2.38 (1H,m), 2.70-2.81 (1H, m), 2.92 (1H, dd, J=14.39, 7.19 Hz), 3.22 (1H, dd,J=14.20, 7.00 Hz), 3.73-3.80 (3H, m), 7.19 (1H, dd, J=1.51, 0.76 Hz),8.08 (1H, d, J=1.51 Hz).

H)5-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiophene-3-carboxylicacid

Methyl5-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiophene-3-carboxylate(73.0 mg) was dissolved in THF (1.5 mL) and methanol (1.5 mL), 2 mol/Laqueous sodium hydroxide solution (0.260 mL) was added at 0° C., and themixture was stirred at room temperature overnight. The reaction mixturewas acidified with 1 mol/L hydrochloric acid, and extracted with ethylacetate. The extract was successively washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give the title compound (66.5 mg).

MS: [M+2H-Boc]⁺ 238.2.

I) tert-butyl (cyclopropylmethyl)(trans-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate

5-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiophene-3-carboxylicacid (33.0 mg), 5-methyl-1,3,4-thiadiazol-2-amine (12.4 mg) andtriethylamine (0.027 mL) were dissolved in DMF (2 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (44.6 mg) was added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate) to give the titlecompound (27.4 mg).

MS: [M+H]⁺ 435.3.

J)5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride

To a mixture of tert-butyl (cyclopropylmethyl)(trans-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate(27.0 mg) and ethyl acetate (2 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (0.310 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure, and the residue was fractionatedwith LC/MS (C18, mobile phase: water/acetonitrile (containing 0.1%TFA)). The obtained fraction was extracted with ethyl acetate andsaturated aqueous sodium hydrogen carbonate solution. The organic layerwas successively washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate, 4 mol/L hydrogen chloride/ethylacetate solution was added, and the mixture was stirred at roomtemperature for 2 hr. The precipitated solid was collected by filtrationand washed with ethyl acetate to give the title compound (22.9 mg)

¹H NMR (300 MHz, DMSO-d₆) δ 0.35-0.44 (2H, m), 0.53-0.64 (2H, m),1.28-1.39 (1H, m), 1.63-1.75 (1H, m), 2.63 (3H, s), 2.80 (1H, ddd,J=9.75, 6.15, 3.79 Hz), 2.90-2.99 (2H, m), 7.51 (1H, s), 8.45 (1H, d,J=1.51 Hz), 9.57 (2H, brs), 10.08 (1H, brs), 12.36-13.00 (1H, m).

Example 24N-(4,4-difluorocyclohexyl)-5-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidehydrochloride A)5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid

Methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(450 mg) was dissolved in methanol (5 mL) and THF (5 mL), 2 mol/Laqueous sodium hydroxide solution (1.89 mL) was added at 0° C., and themixture was stirred at room temperature overnight. The reaction mixturewas acidified with 1 mol/L hydrochloric acid at 0° C. and extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive the title compound (385 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.02-1.23 (2H, m), 1.39 (9H, s), 2.07 (1H,ddd, J=9.09, 6.25, 3.22 Hz), 2.59 (1H, brs), 7.07 (1H, d, J=0.76 Hz),7.28 (1H, brs), 7.97 (1H, d, J=1.51 Hz), 12.61 (1H, brs).

B)N-(4,4-difluorocyclohexyl)-5-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidehydrochloride

By a method similar to that of Example 1, steps G and H and Example 2,the title compound was obtained.

Example 254-(trans-2-aminocyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride

4-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid (50 mg), 1-methyl-1H-pyrazol-4-amine hydrochloride (27 mg) andtriethylamine (0.094 mL) were dissolved in DMF (1.0 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (77 mg) was added at room temperature, and themixture was stirred at room temperature overnight. The reaction mixturewas poured into water, extracted with ethyl acetate, washed with waterand saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. To a mixture of the obtainedresidue and ethyl acetate (2.0 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (2.0 mL) at room temperature, and themixture was stirred at room temperature overnight. The resultingprecipitate was collected by filtration to give the title compound (55mg).

MS: [M-2HCl+H]⁺ 277.1.

Example 26 4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidefumarate

To a mixture of4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride (15 mg) and ethyl acetate was added saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The extract was washed with water and saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. To a mixture of the obtained residue and ethyl acetate wasadded a solution of fumaric acid (4.13 mg) in ethanol at roomtemperature, and the reaction mixture was stirred for 30 min. Theresulting precipitate was collected by filtration to give the titlecompound (9.0 mg).

¹H NMR (300 MHz, METHANOL-d₄) δ 0.26-0.36 (2H, m), 0.58-0.69 (2H, m),1.01-1.12 (1H, m), 1.13-1.22 (1H, m), 1.30-1.40 (1H, m), 2.10-2.20 (1H,m), 2.55 (3H, s), 2.67 (3H, s), 2.72-2.79 (1H, m), 2.83-2.90 (2H, m),6.63-6.72 (1H, m), 7.52-7.65 (1H, m).

Example 274-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride A) ethyl (E)-3-(5-bromothiophen-3-yl)acrylate

To a suspension of lithium chloride (174 mg) and acetonitrile (15 mL)were added 5-bromothiophene-3-carbaldehyde (770 mg) and ethyldiethylphosphonoacetate (0.840 mL) at 0° C., and the mixture was stirredat 0° C. for 10 min. To the reaction mixture was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.638 mL), and the mixture wasstirred at room temperature overnight. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas successively washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (1.01 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.19-1.29 (3H, m), 4.11-4.23 (2H, m), 6.48(1H, d, J=15.90 Hz), 7.53 (1H, d, J=15.0 Hz), 7.74 (1H, d, J=1.51 Hz),7.98 (1H, d, J=1.51 Hz).

B) ethyl trans-2-(5-bromothiophen-3-yl)cyclopropanecarboxylate

To a suspension of trimethylsulfoxonium iodide (1.01 g) in DMSO (10 mL)was added sodium hydride (60% in oil, 184 mg) under a nitrogenatmosphere, and the mixture was stirred at room temperature for 30 min.To the reaction mixture was added a mixture of ethyl(E)-3-(5-bromothiophen-3-yl)acrylate (1.00 g) and DMSO (5 mL), and themixture was stirred at room temperature overnight under a nitrogenatmosphere. Water was added to the reaction mixture at room temperature,and the mixture was extracted with ethyl acetate. The extract wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (263 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.16-1.24 (3H, m), 1.27-1.42 (2H, m), 1.92(1H, ddd, J=8.33, 5.30, 4.16 Hz), 2.44 (1H, ddd, J=9.18, 6.72, 4.16 Hz),4.03-4.14 (2H, m), 7.09 (1H, d, J=1.89 Hz), 7.32 (1H, d, J=1.51 Hz).

C) trans-2-(5-bromothiophen-3-yl)cyclopropanecarboxylic acid

Ethyl trans-2-(5-bromothiophen-3-yl)cyclopropanecarboxylate (260 mg) wasdissolved in THF (2 mL) and ethanol (2 mL), 2 mol/L aqueous sodiumhydroxide solution (1.18 mL) was added at 0° C., and the mixture wasstirred at room temperature overnight. The reaction mixture wasacidified with 1 mol/L hydrochloric acid, and extracted with ethylacetate. The extract was successively washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give the title compound (215 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.22-1.40 (2H, m), 1.78 (1H, ddd, J=8.33,5.30, 4.16 Hz), 2.39 (1H, ddd, J=9.09, 6.44, 4.16 Hz), 7.08 (1H, d,J=1.51 Hz), 7.30 (1H, d, J=1.51 Hz), 12.35 (1H, brs).

D) tert-butyl (trans-2-(5-bromothiophen-3-yl)cyclopropyl)carbamate

To a mixture of trans-2-(5-bromothiophen-3-yl)cyclopropanecarboxylicacid (230 mg) and tert-butyl alcohol (3 mL) were added triethylamine(0.156 mL) and diphenylphosphoryl azide (0.241 mL) at room temperature,and the mixture was stirred at room temperature for 2 hr and then at 80°C. overnight. The reaction mixture was cooled to room temperature, waterwas added, and the mixture was extracted with ethyl acetate. The extractwas successively washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (205 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92-1.10 (2H, m), 1.34-1.41 (9H, m), 1.87(1H, ddd, J=9.28, 6.25, 3.41 Hz), 2.53-2.65 (1H, m), 7.00 (1H, d, J=1.51Hz), 7.12 (1H, d, J=1.51 Hz), 7.20 (1H, brs).

E) methyl4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate

A mixture of tert-butyl(trans-2-(5-bromothiophen-3-yl)cyclopropyl)carbamate (330 mg),triethylamine (0.289 mL),dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (152 mg) andmethanol (30 mL) was stirred at 90° C. for 8 hr under a carbon monoxideatmosphere (3 atm). The insoluble material was filtered off, and thefiltrate was concentrated under reduced pressure. The residue wasextracted with ethyl acetate and water, and the organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate) to give the titlecompound (253 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.99-1.12 (2H, m), 1.38 (9H, s), 1.88-1.98(1H, m), 2.60 (1H, brs), 3.80 (3H, s), 7.22 (1H, brs), 7.50 (1H, d,J=1.51 Hz), 7.59 (1H, d, J=1.51 Hz).

F)4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylicacid

Methyl4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate(250 mg) was dissolved in THF (4 mL) and methanol (4 mL), 2 mol/Laqueous sodium hydroxide solution (1.05 mL) was added at 0° C., and themixture was stirred at room temperature overnight. The reaction mixturewas acidified with 1 mol/L hydrochloric acid at 0° C., and the mixturewas extracted with ethyl acetate. The extract was successively washedwith water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the title compound (235 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.96-1.12 (2H, m), 1.38 (9H, s), 1.92 (1H,ddd, J=9.18, 6.34, 3.03 Hz), 2.58 (1H, brs), 7.22 (1H, brs), 7.39-7.46(1H, m), 7.50 (1H, d, J=1.51 Hz), 12.99 (1H, brs).

G) tert-butyl(trans-2-(5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate

4-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylicacid (80.0 mg), 5-methyl-1,3,4-thiadiazol-2-amine (35.8 mg) andtriethylamine (0.079 mL) were dissolved in DMF (3 mL),0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (129 mg) was added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate) to give the titlecompound (58.2 mg).

MS: [M+H]⁺ 381.2.

H)4-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride

To a mixture of tert-butyl(trans-2-(5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate(55.0 mg) and ethyl acetate (3 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (0.361 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The precipitated solid wascollected by filtration and washed with ethyl acetate to give the titlecompound (26.3 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.11-1.23 (1H, m), 1.44 (1H, ddd, J=10.03,5.87, 4.54 Hz), 2.43 (1H, ddd, J=9.75, 6.15, 3.41 Hz), 2.62 (3H, s),2.81 (1H, dd, J=7.76, 3.98 Hz), 7.73 (1H, s), 7.92-8.19 (1H, m), 8.54(3H, brs).

I) 4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-,3,4-thiadiazol-2-yl)thiophene-2-carboxamide dihydrochloride

To a mixture of4-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride (24.0 mg), sodium hydrogen carbonate (14.3 mg), THF (1.5mL) and methanol (1.5 mL) was added cyclopropanecarbaldehyde (5.71 mg)at room temperature. Under a nitrogen atmosphere, the reaction mixturewas stirred at 60° C. for 1.5 hr and at room temperature for 30 min, andsodium borohydride (3.86 mg) was added at 0° C. The reaction mixture wasstirred at room temperature for 1 hr, and ethyl acetate, water andsaturated aqueous sodium hydrogen carbonate solution were added to thereaction mixture. The mixture was extracted with ethyl acetate, and theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography (ethyl acetate/methanol). To the obtained fraction wasadded 4 mol/L hydrogen chloride/ethyl acetate solution and the reactionmixture was stirred at room temperature overnight. The precipitatedsolid was collected by filtration and washed with ethyl acetate to givethe title compound (17.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.30-0.44 (2H, m), 0.50-0.68 (2H, m),1.05-1.17 (1H, m), 1.19-1.32 (1H, m), 1.52-1.66 (1H, m), 2.55-2.67 (4H,m), 2.86-3.00 (3H, m), 7.75 (1H, s), 8.07 (1H, brs), 9.37-9.60 (2H, m).

Example 284-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamidehydrochloride A) tert-butyl(trans-2-(5-((4,4-difluorocyclohexyl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate

4-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylicacid (150 mg), 4,4-difluorocyclohexanamine hydrochloride (100 mg) andtriethylamine (0.295 mL) were dissolved in DMF (6 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (242 mg) was added at room temperature, and themixture was stirred overnight. To the reaction mixture were added ethylacetate and water, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (211 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92-1.12 (2H, m), 1.33-1.42 (9H, m),1.48-1.69 (2H, m), 1.79-2.14 (7H, m), 2.62 (1H, brs), 3.92 (1H, d,J=7.57 Hz), 7.22 (1H, brs), 7.31 (1H, s), 7.55 (1H, d, J=1.14 Hz), 8.20(1H, d, J=7.95 Hz).

B)4-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamidehydrochloride

To a mixture of tert-butyl(trans-2-(5-((4,4-difluorocyclohexyl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate(210 mg) and ethyl acetate (3 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (1.31 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The precipitated solid wascollected by filtration, washed with ethyl acetate, and dried underreduced pressure to give the title compound (108 mg).

MS: [M-HCl+H]⁺ 301.2.

C)4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamidehydrochloride

To a mixture of4-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamidehydrochloride (30.0 mg), sodium hydrogen carbonate (18.7 mg), THF (1.5mL) and methanol (1.5 mL) was added cyclopropanecarbaldehyde (7.49 mg)at room temperature. Under a nitrogen atmosphere, the reaction mixturewas stirred at 60° C. for 1.5 hr and at room temperature for 30 min, andsodium borohydride (5.05 mg) was added at 0° C. The reaction mixture wasstirred at room temperature for 1 hr, and ethyl acetate, water andsaturated aqueous sodium hydrogen carbonate solution were added to thereaction mixture. The mixture was extracted with ethyl acetate, and theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate), and to the obtained fraction wasadded 4 mol/L hydrogen chloride/ethyl acetate solution. The reactionmixture was stirred at room temperature overnight, and the precipitatedsolid was collected by filtration, washed with ethyl acetate and driedunder reduced pressure to give the title compound (18.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.36 (2H, brs), 0.59 (2H, brs), 0.97-1.34(2H, m), 1.45-1.68 (3H, m), 1.80-2.13 (6H, m), 2.94 (3H, d, J=7.57 Hz),3.92 (2H, brs), 7.44-7.75 (2H, m), 8.23 (1H, d, J=8.33 Hz), 9.19 (1H,brs).

Example 29N-(4,4-difluorocyclohexyl)-4-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-2-carboxamidehydrochloride

To a mixture of4-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamidehydrochloride (30.0 mg), sodium hydrogen carbonate (18.7 mg), THF (1.5mL) and methanol (1.5 mL) was added dihydro-2H-pyran-4(3H)-one (10.7mg). Under a nitrogen atmosphere, the reaction mixture was stirred at60° C. for 1.5 hr and at room temperature for 30 min, and sodiumborohydride (5.05 mg) was added at 0° C. The reaction mixture wasstirred at room temperature for 1 hr, and ethyl acetate, water andsaturated aqueous sodium hydrogen carbonate solution were added to thereaction mixture. The mixture was extracted with ethyl acetate, and theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate), and to the obtained fractionwas added 4 mol/L hydrogen chloride/ethyl acetate solution. The reactionmixture was stirred at room temperature overnight, and the precipitatedsolid was collected by filtration, and washed with ethyl acetate to givethe title compound (14.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.11-1.33 (1H, m), 1.42-2.20 (15H, m), 2.93(1H, brs), 3.38-3.55 (2H, m), 3.92 (3H, d, J=10.60 Hz), 7.43-7.71 (2H,m), 8.23 (1H, d, J=6.82 Hz), 9.43 (1H, brs).

Example 305-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride A) tert-butyl(trans-2-(4-((4,4-difluorocyclohexyl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate

5-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid (100 mg), 4,4-difluorocyclohexanamine hydrochloride (66.6 mg) andtriethylamine (0.197 mL) were dissolved in DMF (4 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (161 mg) was added, and the mixture was stirred atroom temperature overnight. To the reaction mixture were added ethylacetate and water, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (92.1 mg).

MS: [M+H]⁺ 401.2.

B)5-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride

To a mixture of tert-butyl(trans-2-(4-((4,4-difluorocyclohexyl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate(90.0 mg) and ethyl acetate (3 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (0.562 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The precipitated solid wascollected by filtration and washed with ethyl acetate to give the titlecompound (76.8 mg).

MS: [M-HCl+H]⁺ 301.2.

C)5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride

To a mixture of5-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride (30.0 mg), sodium hydrogen carbonate (18.7 mg), THF (1.5mL) and methanol (1.5 mL) was added cyclopropanecarbaldehyde (7.49 mg)at room temperature. Under a nitrogen atmosphere, the reaction mixturewas stirred at 60° C. for 1.5 hr and at room temperature for 30 min, andsodium borohydride (5.05 mg) was added at 0° C. Under a nitrogenatmosphere, the reaction mixture was stirred at room temperature for 1hr, and ethyl acetate, water and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The mixture wasextracted with ethyl acetate, and the extract was successively washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate), andto the obtained fraction was added 4 mol/L hydrogen chloride/ethylacetate solution. The reaction mixture was stirred at room temperatureovernight, and the precipitated solid was collected by filtration, andwashed with ethyl acetate to give the title compound (14.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.38 (2H, m, J=3.41 Hz), 0.58 (2H, d, J=6.44Hz), 1.07 (1H, brs), 1.20-1.38 (1H, m), 1.45-1.68 (3H, m), 1.86 (3H, m),2.03 (3H, m), 2.69 (2H, m), 2.95 (2H, d, J=7.19 Hz), 3.93 (1H, brs),7.28 (1H, s), 7.95 (1H, s), 8.05 (1H, d, J=7.95 Hz), 9.26 (2H, brs).

Example 31N-(4,4-difluorocyclohexyl)-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride

To a mixture of5-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride (30.0 mg), sodium hydrogen carbonate (18.7 mg), THF (1.5mL) and methanol (1.5 mL) was added dihydro-2H-pyran-4(3H)-one (10.7 mg)at room temperature. Under a nitrogen atmosphere, the reaction mixturewas stirred at 60° C. for 1.5 hr and at room temperature for 30 min, andsodium borohydride (5.05 mg) was added at 0° C. The reaction mixture wasstirred at room temperature for 1 hr, and ethyl acetate, water andsaturated aqueous sodium hydrogen carbonate solution were added to thereaction mixture. The mixture was extracted with ethyl acetate, and theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate), and to the obtained fractionwas added 4 mol/L hydrogen chloride/ethyl acetate solution. The reactionmixture was stirred at room temperature overnight, and the precipitatedsolid was collected by filtration, and washed with ethyl acetate to givethe title compound (18.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.25-1.41 (1H, m), 1.62 (5H, d, J=10.60 Hz),1.77-2.15 (9H, m), 2.62-2.80 (1H, m), 2.89-3.08 (1H, m), 3.39-3.59 (1H,m), 3.92 (3H, d, J=9.47 Hz), 7.28 (1H, s), 7.95 (1H, s), 8.04 (1H, d,J=7.95 Hz), 9.44 (2H, brs).

Example 325-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride A) tert-butyl(2-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate

5-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid (50.0 mg), tetrahydro-2H-pyran-4-amine (19.6 mg) and triethylamine(0.049 mL) were dissolved in DMF (2 mL),0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (81.0 mg) was added at room temperature, and themixture was stirred overnight. To the reaction mixture were added ethylacetate and water, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (61.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.99-1.11 (1H, m), 1.12-1.21 (1H, m), 1.39(9H, s), 1.44-1.62 (2H, m), 1.72 (2H, dd, J=12.49, 2.27 Hz), 2.06 (1H,ddd, J=8.99, 5.77, 3.41 Hz), 2.62 (1H, brs), 3.33-3.42 (2H, m),3.80-4.00 (3H, m), 7.17 (1H, s), 7.28 (1H, brs), 7.83 (1H, d, J=1.51Hz), 8.00 (1H, d, J=7.95 Hz).

B)5-(trans-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride

To a mixture of tert-butyl(2-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate(59.0 mg) and ethyl acetate (3 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (0.402 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The precipitated solid wascollected by filtration and washed with ethyl acetate to give the titlecompound (45.5 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.17-1.31 (1H, m), 1.40-1.62 (3H, m),1.64-1.79 (2H, m), 2.55 (1H, td, J=6.44, 3.41 Hz), 2.75-2.88 (1H, m),3.29-3.45 (2H, m), 3.79-4.01 (3H, m), 7.24-7.32 (1H, m), 7.94 (1H, d,J=1.51 Hz), 8.08 (1H, d, J=7.95 Hz), 8.55 (3H, d, J=2.65 Hz).

C)5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride

To a mixture of5-(trans-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride (43.0 mg), sodium hydrogen carbonate (29.8 mg), THF (2 mL)and methanol (2 mL) was added cyclopropanecarbaldehyde (11.9 mg). Undera nitrogen atmosphere, the reaction mixture was stirred at 60° C. for1.5 hr and at room temperature for 30 min, and sodium borohydride (8.06mg) was added at 0° C. Under a nitrogen atmosphere, the reaction mixturewas stirred at room temperature for 1 hr, and ethyl acetate, water andsaturated aqueous sodium hydrogen carbonate solution were added to thereaction mixture. The mixture was extracted with ethyl acetate, and theextract was washed successively with water and saturated brine. Theextract was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate), and to the obtainedfraction was added 4 mol/L hydrogen chloride/ethyl acetate solutionunder ice-cooling. The reaction mixture was stirred at room temperaturefor 2 hr. The precipitated solid was collected by filtration and washedwith ethyl acetate to give the title compound (29.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.31-0.44 (2H, m), 0.51-0.66 (2H, m),0.98-1.15 (1H, m), 1.21-1.38 (1H, m), 1.42-1.66 (3H, m), 1.66-1.81 (2H,m), 2.70 (1H, ddd, J=9.66, 6.25, 3.41 Hz), 2.91-3.01 (3H, m), 3.33-3.45(2H, m), 3.78-4.04 (3H, m), 7.28 (1H, s), 7.95 (1H, d, J=1.51 Hz), 8.06(1H, d, J=7.57 Hz), 9.30 (2H, brs).

Example 335-(trans-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride A) methyl5-(trans-2-((tert-butoxycarbonyl)(cyclobutyl)amino)cyclopropyl)thiophene-3-carboxylate

To a mixture of methyl5-(trans-2-aminocyclopropyl)thiophene-3-carboxylate hydrochloride (100mg), sodium hydrogen carbonate (90.0 mg), THF (4 mL) and methanol (4 mL)was added cyclobutanone (36.0 mg). Under a nitrogen atmosphere, thereaction mixture was stirred at 60° C. for 1.5 hr and at roomtemperature for 30 min, and sodium borohydride (24.3 mg) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hr, andethyl acetate, water and saturated aqueous sodium hydrogen carbonatesolution were added to the reaction mixture. The mixture was extractedwith ethyl acetate, and the extract was successively washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue wasdissolved in THF (3 mL), and triethylamine (0.090 mL) and di-tert-butyldicarbonate (0.120 mL) were added. The reaction mixture was stirred atroom temperature overnight, and the mixture was extracted with ethylacetate and water. The organic layer was washed with saturated brine,and dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (98.9mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.23-1.33 (2H, m), 1.37 (9H, s), 1.45-1.68(2H, m), 2.01-2.32 (5H, m), 2.62 (1H, ddd, J=7.10, 5.02, 3.41 Hz), 3.77(3H, s), 3.92-4.09 (1H, m), 7.14-7.21 (1H, m), 8.08 (1H, d, J=1.51 Hz).

B) 5-(trans-2-((tert-butoxycarbonyl)(cyclobutyl)amino)cyclopropyl)thiophene-3-carboxylic acid

Methyl 5-(trans-2-((tert-butoxycarbonyl)(cyclobutyl)amino)cyclopropyl)thiophene-3-carboxylate (95.0 mg) wasdissolved in THF (2 mL) and methanol (2 mL), 2 mol/L aqueous sodiumhydroxide solution (0.338 mL) was added at 0° C., and the mixture wasstirred at room temperature overnight. The reaction mixture wasacidified with 1 mol/L hydrochloric acid at 0° C., and extracted withethyl acetate. The extract was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give the title compound (90.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.22-1.32 (2H, m), 1.38 (9H, s), 1.48-1.67(2H, m), 2.04-2.30 (5H, m), 2.61 (1H, ddd, J=7.29, 4.45, 3.41 Hz),3.94-4.07 (1H, m), 7.11-7.15 (1H, m), 7.99 (1H, d, J=1.51 Hz), 12.60(1H, brs).

C) tert-butylcyclobutyl(trans-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate

5-(trans-2-((tert-Butoxycarbonyl) (cyclobutyl)amino)cyclopropyl)thiophene-3-carboxylic acid (45.0 mg),5-methyl-1,3,4-thiadiazol-2-amine (18.4 mg) and triethylamine (0.028 mL)were dissolved in DMF (3 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (60.8 mg) was added, and the mixture was stirred atroom temperature overnight. The reaction mixture was extracted withethyl acetate and water, and the organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (38.3mg)

¹H NMR (300 MHz, DMSO-d₆) δ 1.14-1.43 (11H, m), 1.48-1.69 (2H, m),2.04-2.34 (5H, m), 2.58-2.67 (4H, m), 4.03 (1H, quin, J=8.52 Hz), 7.47(1H, s), 8.36 (1H, d, J=1.14 Hz), 12.64 (1H, brs).

D)5-(trans-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride

To a mixture of tert-butylcyclobutyl(trans-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate(36.0 mg) and ethyl acetate (2 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (0.207 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The precipitated solid wascollected by filtration and washed with ethyl acetate to give the titlecompound (26.5 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.17 (1H, t, J=7.00 Hz), 1.26-1.42 (1H, m),1.56-1.68 (1H, m), 1.74-1.92 (2H, m), 2.29 (4H, d, J=13.63), 2.69-3.11(3H, m), 3.60-4.26 (2H, m), 7.42 (1H, s), 8.45 (1H, brs), 9.67-10.18(1H, m), 13.03 (1H, brs).

Example 345-(trans-2-(cyclobutylamino)cyclopropyl)-N-(1-methyl-H-pyrazol-4-yl)thiophene-3-carboxamidehydrochloride A) tert-butylcyclobutyl(trans-2-(4-((1-methyl-1H-pyrazol-4-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate

5-(trans-2-((tert-Butoxycarbonyl)(cyclobutyl)amino)cyclopropyl)thiophene-3-carboxylic acid (45.0 mg),l-methyl-1H-pyrazol-4-amine (15.5 mg) and triethylamine (0.028 mL) weredissolved in DMF (3 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (60.8 mg) was added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate) to give the titlecompound (24.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.35 (2H, m), 1.36-1.42 (9H, m),1.47-1.70 (2H, m), 2.01-2.34 (5H, m), 2.57-2.67 (1H, m), 3.76-3.85 (3H,m), 3.93-4.15 (1H, m), 7.30 (1H, d, J=0.76 Hz), 7.50 (1H, s), 7.93 (2H,s), 10.11 (1H, s).

B)5-(trans-2-(cyclobutylamino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-3-carboxamidehydrochloride

To a mixture of tert-butylcyclobutyl(trans-2-(4-((1-methyl-1H-pyrazol-4-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate(22.0 mg) and ethyl acetate (1 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (0.132 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The precipitated solid wascollected by filtration and washed with ethyl acetate to give the titlecompound (11.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.24-1.38 (1H, m), 1.51-1.66 (1H, m),1.72-1.90 (2H, m), 2.12-2.40 (4H, m), 2.74 (1H, ddd, J=9.94, 6.15, 3.22Hz), 2.82-2.96 (1H, m), 3.75-3.95 (4H, m), 7.29-8.12 (4H, m), 9.76 (2H,brs), 10.26 (1H, s).

Example 35 4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl) thiazole-2-carboxamidehydrochloride A) ethyl (E)-3-(2-bromothiazol-4-yl)acrylate

To a suspension of lithium chloride (450 mg) in acetonitrile (30 mL)were added 2-bromothiazole-4-carbaldehyde (2.00 g) and ethyldiethylphosphonoacetate (2.17 mL) at 0° C., and the mixture was stirredunder a nitrogen atmosphere at 0° C. for 5 min. To the reaction mixturewas added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.65 mL) at 0° C., and themixture was stirred under a nitrogen atmosphere at room temperatureovernight. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was successively washed withwater and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate) to give the titlecompound (2.34 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.25 (3H, t, J=7.00 Hz), 4.19 (2H, q, J=6.94Hz), 6.54 (1H, d, J=15.52 Hz), 7.60 (1H, d, J=15.52 Hz), 8.14 (1H, s).

B) ethyl trans-2-(2-bromothiazol-4-yl)cyclopropanecarboxylate

To a suspension of trimethylsulfoxonium iodide (2.35 g) in DMSO (20 mL)was added sodium hydride (50% in oil, 512 mg) under a nitrogenatmosphere, and the mixture was stirred at room temperature for 30 min.To the reaction mixture was added a mixture of ethyl(E)-3-(2-bromothiazol-4-yl)acrylate (2.33 g) and DMSO (10 mL), and themixture was stirred at room temperature overnight. Water was added tothe reaction mixture at 0° C., and the mixture was extracted with ethylacetate. The extract was successively washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (912mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.16-1.23 (3H, m), 1.39-1.48 (2H, m),1.93-2.03 (1H, m), 2.56-2.65 (1H, m), 4.09 (2H, q, J=6.94 Hz), 7.56 (1H,s).

C) trans-2-(2-bromothiazol-4-yl)cyclopropanecarboxylic acid

Ethyl trans-2-(2-bromothiazol-4-yl)cyclopropanecarboxylate (905 mg) wasdissolved in THF (5 mL) and ethanol (5 mL), 2 mol/L aqueous sodiumhydroxide solution (4.10 mL) was added at 0° C., and the mixture wasstirred at room temperature overnight. The reaction mixture wasacidified with 1 mol/L hydrochloric acid, and extracted with ethylacetate. The extract was successively washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give the title compound (809 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.32-1.45 (2H, m), 1.88 (1H, ddd, J=8.24,5.40, 4.16 Hz), 2.53-2.60 (1H, m), 7.54 (1H, s), 12.42 (1H, brs).

D) tert-butyl (trans-2-(2-bromothiazol-4-yl)cyclopropyl)carbamate

To a mixture of trans-2-(2-bromothiazol-4-yl)cyclopropanecarboxylic acid(805 mg) and tert-butyl alcohol (10 mL) were added triethylamine (0.543mL) and diphenylphosphoryl azide (0.838 mL) at room temperature, and themixture was stirred at room temperature for 2 hr and then at 80° C.overnight. The reaction mixture was cooled to room temperature, waterwas added, and the mixture was extracted with ethyl acetate. The extractwas successively washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (514 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.05-1.14 (2H, m), 1.37 (9H, s), 2.06 (1H,td, J=7.57, 3.03 Hz), 2.79 (1H, brs), 7.24 (1H, brs), 7.36 (1H, s).

E) trans-2-(2-bromothiazol-4-yl)cyclopropanamine hydrochloride

To a mixture of tert-butyl(trans-2-(2-bromothiazol-4-yl)cyclopropyl)carbamate (200 mg) and ethylacetate (3 mL) was added 4 mol/L hydrogen chloride/ethyl acetatesolution (1.57 mL) at 0° C., and the mixture was stirred at roomtemperature overnight. The precipitated solid was collected byfiltration and washed with ethyl acetate to give the title compound (158mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.24 (1H, dt, J=7.95, 6.06 Hz), 1.36-1.46(1H, m), 2.56 (1H, ddd, J=9.75, 6.15, 3.41 Hz), 2.81-2.95 (1H, m), 7.56(1H, s), 8.54 (3H, brs).

F) trans-2-(2-bromothiazol-4-yl)-N-(cyclopropylmethyl)cyclopropanamine

A mixture of trans-2-(2-bromothiazol-4-yl)cyclopropanamine hydrochloride(100 mg), sodium hydrogen carbonate (131 mg), THF (3 mL) and methanol (3mL) was stirred at room temperature for 30 min, andcyclopropanecarbaldehyde (32.9 mg) was added. Under a nitrogenatmosphere, the reaction mixture was stirred at 60° C. for 2 hr, andsodium borohydride (22.2 mg) was added at 0° C. Under a nitrogenatmosphere, the reaction mixture was stirred at room temperature for 1.5hr, and ethyl acetate and water were added to the reaction mixture underice-cooling. The mixture was extracted with ethyl acetate, and theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, hexane/ethyl acetate) to give the title compound(84.4 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.02-0.09 (2H, m), 0.33-0.41 (2H, m),0.76-0.89 (1H, m), 0.90-1.03 (2H, m), 1.87-2.02 (1H, m), 2.36-2.47 (4H,m), 7.27 (1H, s).

G) tert-butyl (trans-2-(2-bromothiazol-4-yl)cyclopropyl)(cyclopropylmethyl)carbamate

trans-2-(2-Bromothiazol-4-yl)-N-(cyclopropylmethyl)cyclopropanamine(81.0 mg) was dissolved in THF (4 mL), and triethylamine (0.062 mL) anddi-tert-butyl dicarbonate (0.103 mL) were added. The reaction mixturewas stirred at room temperature overnight, and extracted with ethylacetate and water. The organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate) to give the titlecompound (106 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.06-0.28 (2H, m), 0.33-0.53 (2H, m),0.87-1.03 (1H, m), 1.24 (2H, dd, J=7.57, 6.44 Hz), 1.35 (9H, s),2.18-2.33 (1H, m), 2.79-2.99 (2H, m), 3.21 (1H, dd, J=14.39, 6.82 Hz),7.44 (1H, s).

H) methyl4-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiazole-2-carboxylate

A mixture of tert-butyl (trans-2-(2-bromothiazol-4-yl)cyclopropyl)(cyclopropylmethyl)carbamate (80.0 mg), triethylamine (0.060 mL),dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (31.4 mg) andmethanol (15 mL) was stirred at 90° C. for 8 hr under a carbon monoxideatmosphere (3 atm). After cooling to room temperature, the insolublematerial was filtered off, and the filtrate was concentrated underreduced pressure. The residue was extracted with ethyl acetate andwater, and the organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (76.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.05-0.28 (2H, m), 0.32-0.53 (2H, m),0.87-1.05 (1H, m), 1.27-1.37 (11H, m), 2.36 (1H, td, J=7.86, 3.22 Hz),2.87-3.03 (2H, m), 3.22 (1H, dd, J=14.39, 6.82 Hz), 3.82-3.93 (3H, m),7.85 (1H, s).

I)4-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiazole-2-carboxylicacid

Methyl4-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiazole-2-carboxylate(93.0 mg) was dissolved in methanol (5 mL), 2 mol/L aqueous sodiumhydroxide solution (0.330 mL) was added at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was acidifiedwith 1 mol/L hydrochloric acid at 0° C., and extracted with ethylacetate. The extract was successively washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give the title compound (78.9 mg).

MS: [M+H]⁺ 339.2.

J) tert-butyl (cyclopropylmethyl)(trans-2-(2-((4,4-difluorocyclohexyl)carbamoyl)thiazol-4-yl)cyclopropyl)carbamate

4-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiazole-2-carboxylic acid (38.0mg), 4,4-difluorocyclohexanamine hydrochloride (21.2 mg) andtriethylamine (0.063 mL) were dissolved in DMF (3 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (51.2 mg) was added, and the mixture was stirred atroom temperature overnight. To the reaction mixture were added ethylacetate and water, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (17.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.07-0.28 (2H, m), 0.32-0.54 (2H, m),0.90-1.04 (1H, m), 1.23-1.42 (11H, m), 1.64-1.95 (5H, m), 1.99-2.12 (3H,m), 2.29 (1H, ddd, J=9.47, 6.25, 3.22 Hz), 2.94-3.07 (2H, m), 3.10-3.25(1H, m), 3.96 (1H, d, J=7.95 Hz), 7.66 (1H, s), 8.54 (1H, d, J=8.71 Hz).

K) 4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiazole-2-carboxamidehydrochloride

To a mixture of tert-butyl (cyclopropylmethyl)(trans-2-(2-((4,4-difluorocyclohexyl)carbamoyl)thiazol-4-yl)cyclopropyl)carbamate(16.0 mg) and ethyl acetate (1.5 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (0.088 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The precipitated solid wascollected by filtration and washed with ethyl acetate to give the titlecompound (10.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.36 (2H, d, J=4.16 Hz), 0.57 (2H, d, J=6.44Hz), 1.00-1.18 (1H, m), 1.33-1.49 (1H, m), 1.55-1.67 (1H, m), 1.68-1.87(4H, m), 2.05 (3H, brs), 2.76-2.85 (1H, m), 2.94 (2H, d, J=6.44 Hz),3.13 (1H, brs), 3.97 (2H, brs), 7.78 (1H, s), 8.59 (1H, d, J=8.71 Hz),9.33-9.67 (2H, m).

Example 365-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamidehydrochloride A) trans-2-(5-bromothiophen-2-yl)cyclopropanecarboxylicacid

To a mixture of lithium hydroxide monohydrate (12.7 g), water (100 mL)and methanol (100 mL) was added ethyltrans-2-(5-bromothiophen-2-yl)cyclopropanecarboxylate (16.7 g) at roomtemperature. After stirring at room temperature for 24 hr, methanol wasevaporated under reduced pressure. The aqueous layer was washed withdichloromethane, acidified with 2 mol/L hydrochloric acid, and extractedwith ethyl acetate. The extract was dried over anhydrous sodium sulfate,and concentrated under reduced pressure to give the title compound (14.7g).

¹H NMR (400 MHz, CDCl₃) δ 1.35-1.40 (1H, m), 1.65-1.69 (1H, m),1.90-1.94 (1H, m), 2.67-2.72 (1H, m), 6.61 (1H, d, J=3.6 Hz), 6.87 (1H,d, J=3.6 Hz).

B) tert-butyl (2-(5-bromothiophen-2-yl)cyclopropyl)carbamate

trans-2-(5-Bromothiophen-2-yl)cyclopropanecarboxylic acid (14.7 g) wasdissolved in acetone (150 mL), triethylamine (9.03 g) was added, andthen ethyl chloroformate (9.68 g) was added at −20° C. After stirring at−10° C. to −20° C. for 2 hr, a mixture of sodium azide (6.57 g) andwater (20 mL) was added, and the mixture was stirred at −10° C. to −20°C. for 3 hr. Acetone was evaporated by concentration under reducedpressure, and water (150 mL) and toluene (150 mL) were added. Theaqueous layer was extracted twice with toluene (100 mL). The combinedextract was dried over anhydrous sodium sulfate and concentrated to 150mL under reduced pressure. To the obtained mixture was added tert-butylalcohol (25 mL), and the mixture was heated under reflux for 18 hr. Themixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (petroleum ether/ethylacetate) to give the title compound (8.66 g).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (2H, t, J=6.8 Hz), 1.46 (9H, s),2.08-2.13 (1H, m), 2.67-2.74 (1H, m), 4.81 (1H, s), 6.57 (1H, d, J=3.2Hz), 6.82 (1H, d, J=3.2 Hz).

C) trans-2-(5-bromothiophen-2-yl)cyclopropanamine hydrochloride

To a mixture of tert-butyl(2-(5-bromothiophen-2-yl)cyclopropyl)carbamate (200 mg) and ethylacetate (5 mL) was added 4 mol/L hydrogen chloride/ethyl acetatesolution (1.57 mL) at 0° C., and the mixture was stirred at roomtemperature overnight. The precipitated solid was collected byfiltration and washed with ethyl acetate to give the title compound (135mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (1H, dt, J=7.95, 6.25 Hz), 1.36-1.51(1H, m), 2.47-2.54 (1H, m), 2.73-2.85 (1H, m), 6.75 (1H, dd, J=3.79,1.14 Hz), 6.99-7.10 (1H, m), 8.50 (2H, brs).

D) tert-butyl (2-trans-(5-bromothiophen-2-yl)cyclopropyl)(cyclopropylmethyl)carbamate

To a mixture of trans-2-(5-bromothiophen-2-yl)cyclopropanaminehydrochloride (130 mg), sodium hydrogen carbonate (107 mg), THF (4 mL)and methanol (4 mL) was added cyclopropanecarbaldehyde (43.0 mg) at roomtemperature. Under a nitrogen atmosphere, the reaction mixture wasstirred at 60° C. for 1.5 hr and then at room temperature for 30 min,and sodium borohydride (29.0 mg) was added at 0° C. The reaction mixturewas stirred at room temperature for 1 hr, and ethyl acetate, water andsaturated aqueous sodium hydrogen carbonate solution were added to thereaction mixture. The mixture was extracted with ethyl acetate, and theextract was successively washed with water and saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was dissolved in THF (5 mL),triethylamine (0.094 mL) and di-tert-butyl dicarbonate (0.156 mL) wereadded, and the mixture was stirred at room temperature overnight. To thereaction mixture were added ethyl acetate and water, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (160mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.08-0.27 (2H, m), 0.35-0.52 (2H, m),0.88-1.06 (1H, m), 1.14-1.24 (1H, m), 1.25-1.34 (1H, m), 1.39 (9H, s),2.20-2.32 (1H, m), 2.65-2.77 (1H, m), 2.93 (1H, dd, J=14.39, 6.82 Hz),3.18 (1H, dd, J=14.39, 6.82 Hz), 6.71 (1H, dd, J=3.79, 0.76 Hz), 7.02(1H, d, J=3.79 Hz).

E) methyl5-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiophene-2-carboxylate

A mixture of tert-butyl (2-trans-(5-bromothiophen-2-yl)cyclopropyl)(cyclopropylmethyl)carbamate (155 mg), triethylamine (0.116 mL),dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (60.9 mg) andmethanol (15 mL) was stirred at 90° C. for 8 hr under a carbon monoxideatmosphere (3 atm). After cooling to room temperature, the insolublematerial was filtered off, and the filtrate was concentrated underreduced pressure. The residue was extracted with ethyl acetate andwater, and the organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (138 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.06-0.30 (2H, m), 0.33-0.52 (2H, m),0.84-1.05 (1H, m), 1.23-1.33 (1H, m), 1.35-1.49 (10H, m), 2.39 (1H, ddd,J=9.47, 6.25, 3.22 Hz), 2.76-2.87 (1H, m), 2.88-3.02 (1H, m), 3.20 (1H,dd, J=14.20, 7.00 Hz), 3.73-3.82 (3H, m), 6.96 (1H, d, J=3.79 Hz), 7.63(1H, d, J=3.79 Hz).

F) 5-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiophene-2-carboxylic acid

Methyl5-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiophene-2-carboxylate(130 mg) was dissolved in methanol (5 mL), 2 mol/L aqueous sodiumhydroxide solution (0.462 mL) was added at 0° C., and the mixture wasstirred at room temperature overnight. The reaction mixture wasacidified with 1 mol/L hydrochloric acid at 0° C., and extracted withethyl acetate. The extract was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give the title compound (125 mg).

MS: [M+2H-(Boc)]⁺ 238.2.

G) tert-butyl (cyclopropylmethyl)(trans-2-(5-((4,4-difluorocyclohexyl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate

5-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiophene-2-carboxylic acid (35.0mg), 4,4-difluorocyclohexanamine hydrochloride (19.6 mg) andtriethylamine (0.058 mL) were dissolved in DMF (3 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (47.3 mg) was added, and the mixture was stirred atroom temperature overnight. To the reaction mixture were added ethylacetate and water, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (42.3 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.08-0.28 (2H, m), 0.34-0.52 (2H, m),0.88-1.04 (1H, m), 1.18-1.27 (1H, m), 1.32-1.42 (10H, m), 1.50-1.69 (2H,m), 1.77-1.96 (3H, m), 1.97-2.13 (3H, m), 2.32 (1H, m), 2.70-2.80 (1H,m), 2.89-3.04 (1H, m), 3.10-3.26 (1H, m), 3.91 (1H, d, J=7.57 Hz), 6.86(1H, d, J=3.79 Hz), 7.58 (1H, d, J=3.79 Hz), 8.16 (1H, d, J=7.57 Hz).

H)5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamidehydrochloride

tert-Butyl (cyclopropylmethyl)(trans-2-(5-((4,4-difluorocyclohexyl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate(40.0 mg) was dissolved in ethyl acetate (3 mL), 4 mol/L hydrogenchloride/ethyl acetate solution (0.220 mL) was added at 0° C., and themixture was stirred at room temperature for 4 hr. The precipitated solidwas collected by filtration and washed with ethyl acetate to give thetitle compound (22.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.31-0.44 (2H, m), 0.51-0.64 (2H, m),0.97-1.15 (1H, m), 1.23-1.40 (1H, m), 1.50-1.72 (3H, m), 1.78-2.10 (6H,m), 2.74 (1H, ddd, J=9.84, 6.25, 3.60 Hz), 2.87-3.05 (3H, m), 3.82-4.00(1H, m), 6.93 (1H, d, J=3.79 Hz), 7.63 (1H, d, J=3.79 Hz), 8.25 (1H, d,J=7.95 Hz), 9.39 (2H, brs).

Example 37 5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride A) tert-butyl (cyclopropylmethyl)(trans-2-(5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate

5-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)thiophene-2-carboxylic acid (35.0mg), 5-methyl-1,3,4-thiadiazol-2-amine (13.1 mg) and triethylamine(0.029 mL) were dissolved in DMF (3 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (47.3 mg) was added, and the mixture was stirred atroom temperature overnight. To the reaction mixture were added ethylacetate and water, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (23.7 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.08-0.31 (2H, m), 0.35-0.53 (2H, m),0.90-1.07 (1H, m), 1.20-1.50 (11H, m), 2.33-2.45 (1H, m), 2.62 (3H, s),2.78-2.88 (1H, m), 2.90-3.07 (1H, m), 3.19 (1H, dd, J=14.39, 6.82 Hz),6.98 (1H, d, J=3.79 Hz), 8.08 (1H, brs), 12.85 (1H, brs).

B)5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride

To a mixture of tert-butyl (cyclopropylmethyl)(trans-2-(5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate(22.0 mg) and ethyl acetate (2 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (0.127 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The precipitated solid wascollected by filtration, and washed with ethyl acetate and methanol togive the title compound (10.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.32-0.44 (2H, m), 0.51-0.65 (2H, m),0.97-1.19 (1H, m), 1.30-1.45 (1H, m), 1.65-1.81 (1H, m), 2.62 (3H, s),2.78-2.90 (1H, m), 2.96 (2H, d, J=5.68 Hz), 3.01-3.11 (1H, m), 3.86 (2H,s), 7.06 (1H, d, J=3.79 Hz), 8.09 (1H, s), 9.55 (2H, brs).

Example 38N-cyclopentyl-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)] A) methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long) B) methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Short)

A racemate (16.9 g) of methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylatewas fractionated by SFC (column: CHIRALPAK AD, 20 mmID×250 mmL,manufactured by Daicel Corporation, mobile phase: carbondioxide/methanol=820/180), and the obtained fraction was concentratedunder reduced pressure to give the title compound (7.23 g) having ashort retention time and the title compound (7.39 g) having a longretention time.

methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)

¹H NMR (300 MHz, DMSO-d₆) δ 1.07-1.25 (2H, m), 1.39 (9H, s), 2.08 (1H,ddd, J=9.09, 6.25, 3.22 Hz), 2.60 (1H, d, J=5.30 Hz), 3.76 (3H, s),7.08-7.14 (1H, m), 7.29 (1H, brs), 8.07 (1H, d, J=1.14 Hz).

HPLC retention time 2.859 min (column: CHIRALPAK ADH (trade name), 4.6mmID×150 mmL, mobile phase: carbon dioxide/methanol=820/180, flow rate:4.0 mL/min, temperature: 35° C., detection: UV 220 nm, concentration:0.5 mg/mL, injection volume: 0.005 mL).

methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time short)

¹H NMR (300 MHz, DMSO-d₆) δ 1.08-1.24 (2H, m), 1.39 (9H, s), 2.08 (1H,ddd, J=8.99, 6.15, 3.03 Hz), 2.60 (1H, brs), 3.77 (3H, s), 7.12 (1H, dd,J=1.51, 0.76 Hz), 7.29 (1H, brs), 8.07 (1H, d, J=1.14 Hz).

HPLC retention time 1.950 min (column: CHIRALPAK ADH (trade name), 4.6mmID×150 mmL, mobile phase: carbon dioxide/methanol=820/180, flow rate:4.0 mL/min, temperature: 35° C., detection: UV 220 nm, concentration:0.5 mg/mL, injection volume: 0.005 mL).

Methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long) was clarified to be methyl5-((1R,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate.

Methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time short) was clarified to be methyl5-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate.

C)5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

Methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long) (458 mg) was dissolved in methanol(5 mL), 2 mol/L aqueous sodium hydroxide solution (1.93 mL) was added at0° C., and the mixture was stirred at room temperature overnight. Thereaction mixture was acidified with 1 mol/L hydrochloric acid at 0° C.,and extracted with ethyl acetate. The extract was successively washedwith water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the title compound (435 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.05-1.22 (2H, m), 1.39 (9H, s), 2.07 (1H,ddd, J=9.09, 6.06, 3.03 Hz), 2.59 (1H, d, J=7.57 Hz), 7.05-7.09 (1H, m),7.28 (1H, brs), 7.97 (1H, d, J=1.51 Hz), 12.61 (1H, brs).

5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to be5-((1R,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid.

D) tert-butyl(trans-2-(4-(cyclopentylcarbamoyl)thiophen-2-yl)cyclopropyl)carbamate[Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

5-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] (70.0 mg), cyclopentanamine (23.1mg) and triethylamine (0.069 mL) were dissolved in DMF (3 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (113 mg) was added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (77.8 mg).

MS: [M+H]⁺ 351.3.

tert-Butyl(trans-2-(4-(cyclopentylcarbamoyl)thiophen-2-yl)cyclopropyl)carbamate[optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to be tert-butyl((1R,2R)-2-(4-(cyclopentylcarbamoyl)thiophen-2-yl)cyclopropyl)carbamate.

E) 5-(trans-2-aminocyclopropyl)-N-cyclopentylthiophene-3-carboxamidehydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

To a mixture of tert-butyl(trans-2-(4-(cyclopentylcarbamoyl)thiophen-2-yl)cyclopropyl)carbamate[optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] (75.0 mg) and ethyl acetate (2mL) was added 4 mol/L hydrogen chloride/ethyl acetate solution (0.535mL) at 0° C., and the mixture was stirred at room temperature overnight.The precipitated solid was collected by filtration and washed with ethylacetate to give the title compound (56.2 mg).

MS: [M+H-(HCl)]⁺ 251.2.

5-(trans-2-Aminocyclopropyl)-N-cyclopentylthiophene-3-carboxamidehydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to be5-((1R,2R)-2-aminocyclopropyl)-N-cyclopentylthiophene-3-carboxamidehydrochloride.

F)N-cyclopentyl-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

To a mixture of5-(trans-2-aminocyclopropyl)-N-cyclopentylthiophene-3-carboxamidehydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] (53.0 mg), sodium hydrogencarbonate (38.8 mg), THF (3 mL) and methanol (3 mL) was addeddihydro-2H-pyran-4(3H)-one (22.2 mg) at room temperature. Under anitrogen atmosphere, the reaction mixture was stirred at 60° C. for 1.5hr and at room temperature for 30 min, and sodium borohydride (10.5 mg)was added at 0° C. The reaction mixture was stirred at room temperaturefor 1 hr, and ethyl acetate, water and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The mixture wasextracted with ethyl acetate, and the extract was successively washedwith water and saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/methanol),and to the obtained fraction was added 4 mol/L hydrogen chloride/ethylacetate solution. The reaction mixture was stirred at room temperatureovernight, and the precipitated solid was collected by filtration, andwashed with ethyl acetate to give the title compound (38.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.28-1.39 (1H, m), 1.39-1.75 (9H, m),1.78-1.92 (2H, m), 1.93-2.06 (2H, m), 2.73 (1H, ddd, J=9.75, 6.34, 3.60Hz), 2.99 (1H, brs), 3.24-3.34 (2H, m), 3.47 (1H, brs), 3.85-4.02 (2H,m), 4.15 (1H, sxt, J=6.74 Hz), 7.29 (1H, s), 7.94 (1H, d, J=1.14 Hz),8.02 (1H, d, J=7.19 Hz), 9.54 (2H, brs).

N-Cyclopentyl-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to beN-cyclopentyl-5-((1R,2R)-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride

Example 39N-cyclopentyl-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Short)]

By a method similar to that of Example 38, the title compound wasobtained.

N-Cyclopentyl-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time short)] was clarified to beN-cyclopentyl-5-((1S,2S)-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamide.

Example 40N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)] A) tert-butyl(trans-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate[Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

5-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] (70.0 mg),5-methyl-1,3,4-thiadiazol-2-amine (31.3 mg) and triethylamine (0.069 mL)were dissolved in DMF (3 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (113 mg) was added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (37.6 mg).

MS: [M+H]⁺ 381.2.

tert-Butyl(trans-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate[optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to be tert-butyl((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate.

B)5-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

To a mixture of tert-butyl(trans-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate[optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] (37.6 mg), ethyl acetate (2 mL)and methanol (2 mL) was added 4 mol/L hydrogen chloride/ethyl acetatesolution (0.247 mL) at 0° C., and the mixture was stirred at roomtemperature overnight. The precipitated solid was collected byfiltration and washed with ethyl acetate to give the title compound(34.5 mg).

MS: [M+H-(2HCl)]⁺ 281.1.

5-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to be5-((1R,2R)-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride.

C)N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

To a mixture of5-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] (33.0 mg), sodium hydrogencarbonate (19.6 mg), THF (2 mL) and methanol (2 mL) was addedtetrahydro-2H-pyran-4-carbaldehyde (12.8 mg) at room temperature. Undera nitrogen atmosphere, the reaction mixture was stirred at 60° C. for1.5 hr and at room temperature for 30 min, and sodium borohydride (5.30mg) was added at 0° C. The reaction mixture was stirred at roomtemperature for 1 hr, and ethyl acetate, water and saturated aqueoussodium hydrogen carbonate solution were added to the reaction mixture.The mixture was extracted with ethyl acetate, and the extract wassuccessively washed with water and saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/methanol), and to the obtained fraction was added 4 mol/Lhydrogen chloride/ethyl acetate solution. The reaction mixture wasstirred at room temperature overnight. The precipitated solid wascollected by filtration and washed with ethyl acetate to give the titlecompound (19.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.16-1.41 (3H, m), 1.60-1.77 (3H, m),1.84-2.06 (1H, m), 2.63 (3H, s), 2.70-2.84 (1H, m), 2.94-3.11 (3H, m),3.29 (2H, t, J=11.93 Hz), 3.90-4.00 (2H, m), 7.51 (1H, s), 8.46 (1H, s),9.26 (2H, brs).

N-(5-Methyl-1,3,4-thiadiazol-2-yl)-5-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to beN-(5-methyl-1,3,4-thiadiazol-2-yl)-5-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride.

Example 41N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Short)]

By a method similar to that of Example 40, the title compound wasobtained.

N-(5-Methyl-1,3,4-thiadiazol-2-yl)-5-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time short)] was clarified to beN-(5-methyl-1,3,4-thiadiazol-2-yl)-5-((1S,2S)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride.

Example 425-(trans-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)] A) tert-butyl(trans-2-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate[Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

5-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] (70.0 mg) was dissolved in DMF (3mL). Tetrahydro-2H-pyran-4-amine (27.5 mg), triethylamine (0.069 mL) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (113 mg) were added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (71.8 mg).

MS: [M+H]⁺ 367.2.

tert-Butyl(trans-2-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate[optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to be tert-butyl((1R,2R)-2-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate.

B)5-(trans-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidedihydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

To a mixture of tert-butyl(trans-2-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate[optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] (69.5 mg) and ethyl acetate (2mL) was added 4 mol/L hydrogen chloride/ethyl acetate solution (0.474mL) at 0° C., and the mixture was stirred at room temperature overnight.The precipitated solid was collected by filtration and washed with ethylacetate to give the title compound (53.6 mg).

MS: [M+H-(2HCl)]⁺ 267.2.

5-(trans-2-Aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidedihydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to be5-((1R,2R)-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidedihydrochloride.

C)5-(trans-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Long)]

To a mixture of5-(trans-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidedihydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] (51.0 mg), sodium hydrogencarbonate (35.4 mg), THF (2 mL) and methanol (2 mL) was addedcyclobutanone (14.2 mg) at room temperature. Under a nitrogenatmosphere, the reaction mixture was stirred at 60° C. for 1.5 hr and atroom temperature for 30 min, and sodium borohydride (9.56 mg) was addedat 0° C. The reaction mixture was stirred at room temperature for 1 hr,and ethyl acetate, water and saturated aqueous sodium hydrogen carbonatesolution were added to the reaction mixture. The mixture was extractedwith ethyl acetate, and the extract was successively washed with waterand saturated brine and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/methanol), and to theobtained fraction was added 4 mol/L hydrogen chloride/ethyl acetatesolution. The reaction mixture was stirred at room temperatureovernight. The precipitated solid was collected by filtration and washedwith ethyl acetate to give the title compound (28.7 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.03 (2H, d, J=6.06 Hz), 1.22-1.36 (1H, m),1.43-1.62 (3H, m), 1.65-1.91 (4H, m), 2.11-2.32 (4H, m), 2.65 (1H, brs),2.85 (1H, d, J=3.41 Hz), 3.77-4.00 (4H, m), 7.26 (1H, s), 7.95 (1H, s),8.05 (1H, d, J=7.95 Hz), 9.49 (2H, brs).

5-(trans-2-(Cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time long)] was clarified to be5-((1R,2R)-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride.

Example 435-(trans-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride [Optical Isomer, Compound Derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(Optical Isomer, Retention Time Short)]

By a method similar to that of Example 42, the title compound wasobtained.

5-(trans-2-(Cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride [optical isomer, compound derived from methyl5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate(optical isomer, retention time short)] was clarified to be5-((1S,2S)-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride.

Example 44N-(4,4-difluorocyclohexyl)-5-((1R,2R)-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride A) tert-butyl((1R,2R)-2-(4-((4,4-difluorocyclohexyl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate

5-((1R,2R)-2-((tert-Butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid (400 mg) was dissolved in DMF (10 mL), 4,4-difluorocyclohexanaminehydrochloride (291 mg), triethylamine (0.59 mL) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (644 mg) were added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure to give thetitle compound (680 mg). The title compound was used for the nextreaction without further purification.

MS: [M-tBu(C₄H₉)+2H]⁺ 345.1.

B)5-((1R,2R)-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride

tert-Butyl((1R,2R)-2-(4-((4,4-difluorocyclohexyl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate(680 mg) and 4 mol/L hydrogen chloride/ethyl acetate solution (1.7 mL)were stirred at room temperature overnight. The precipitated solid wascollected by filtration to give the title compound (500 mg).

MS: [M+H-(HCl)]⁺ 301.1.

C)N-(4,4-difluorocyclohexyl)-5-((1R,2R)-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride

To a mixture of5-((1R,2R)-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride (62.0 mg), borane-2-picoline complex (29.5 mg), methanol(2.0 mL) and acetic acid (0.2 mL) was added dihydro-2H-pyran-4(3H)-one(58.2 mg) at room temperature. The reaction mixture was stirred at roomtemperature for 18 hr, and saturated aqueous sodium hydrogen carbonatesolution was added at 0° C. The mixture was extracted with ethylacetate, and the extract was successively washed with water andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by NH silicagel column chromatography (ethyl acetate/hexane), and to the obtainedfraction was added 4 mol/L hydrogen chloride/ethyl acetate solution. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was crystallized from ethanol/heptane to give the titlecompound (40.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.27-1.41 (1H, m), 1.49-1.72 (5H, m),1.77-2.16 (8H, m), 2.61-2.73 (1H, m), 2.89-3.08 (1H, m), 3.26-3.39 (2H,m), 3.40-3.55 (1H, m), 3.83-4.02 (3H, m), 7.24-7.31 (1H, m), 7.92-7.98(1H, m), 7.99-8.08 (1H, m), 8.99-9.48 (2H, m).

The compounds of Examples 45 to 59 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 455-((1R,2R)-2-(cis-(4-aminocyclohexyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidedihydrochloride

or

5-((1R,2R)-2-(trans-(4-aminocyclohexyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidedihydrochloride Example 465-((1R,2R)-2-(trans-(4-aminocyclohexyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidedihydrochloride

or

5-((1R,2R)-2-(cis-(4-aminocyclohexyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidedihydrochloride Example 475-((1R,2R)-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride Example 485-((1R,2R)-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride Example 49N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-((1R,2R)-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride Example 50N-(2-methyl-1,3-thiazol-5-yl)-5-((1R,2R)-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride Example 51N-(4,4-difluorocyclohexyl)-5-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidehydrochloride Example 525-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-3-carboxamidehydrochloride Example 53N-(2-methyl-1,3-thiazol-5-yl)-5-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride Example 54N-(1,3-dimethyl-1H-pyrazol-4-yl)-5-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride Example 55N-(1,5-dimethyl-1H-pyrazol-4-yl)-5-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride Example 56N-cyclopropyl-5-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidehydrochloride Example 574-(trans-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidehydrochloride Example 58N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamidehydrochloride Example 594-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride Example 603-(4-((((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)-2-thienyl)cyclopropyl)amino)methyl)piperidin-1-yl)propanoicacid trihydrochloride A) tert-butyl4-((((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate

By a method similar to that of Example 2, the title compound wasobtained.

MS: [M+H]⁺ 478.3.

B) tert-butyl4-((2,2,2-trifluoro-N-((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)acetamido)methyl)piperidine-1-carboxylate

To a mixture of tert-butyl4-((((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate(301 mg), triethylamine (127.0 mg) and THF (4.0 mL) was addedtrifluoroacetic anhydride (355.0 mg) at room temperature. The reactionmixture was stirred at room temperature for 18 hr, and saturated aqueoussodium hydrogen carbonate solution was added at 0° C. The mixture wasextracted with ethyl acetate, and the extract was successively washedwith water and saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to give the title compound (213.0 mg).

MS: [M+H]⁺ 574.1.

C)N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-((1R,2R)-2-(2,2,2-trifluoro-N-(piperidin-4-ylmethyl)acetamido)cyclopropyl)thiophene-3-carboxamidehydrochloride

By a method similar to that of Example 1, step H, the title compound wasobtained.

MS: [M-HCl+H]⁺ 474.1.

D) tert-butyl3-(4-((2,2,2-trifluoro-N-((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)acetamido)methyl)piperidin-1-yl)propanoate

To a mixture ofN-(5-methyl-1,3,4-thiadiazol-2-yl)-5-((1R,2R)-2-(2,2,2-trifluoro-N-(piperidin-4-ylmethyl)acetamido)cyclopropyl)thiophene-3-carboxamidehydrochloride (50.0 mg), triethylamine (10.9 mg) and ethanol (2.0 mL)was added tert-butyl acrylate (12.6 mg) at room temperature. Thereaction mixture was stirred at room temperature overnight, and thesolvent was evaporated under reduced pressure. To the residue were addedethyl acetate and saturated aqueous sodium hydrogen carbonate solution,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (44.0 mg).

MS: [M+H]⁺ 602.1.

E) tert-butyl3-(4-((((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propanoate

To a mixture of tert-butyl3-(4-((2,2,2-trifluoro-N-((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)acetamido)methyl)piperidin-1-yl)propanoate(44.0 mg), methanol (1.0 mL) and THF (1.0 mL) was added 1 mol/L aqueoussodium hydroxide solution (1.0 mL) at room temperature. The reactionmixture was stirred at room temperature for 10 min, and water was addedat room temperature. The mixture was extracted with ethyl acetate, andthe extract was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive the title compound (30.0 mg).

MS: [M+H]⁺ 506.2.

F)3-(4-((((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)-2-thienyl)cyclopropyl)amino)methyl)piperidin-1-yl)propanoicacid trihydrochloride

A mixture of tert-butyl3-(4-((((1R,2R)-2-(4-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-2-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propanoate(30.0 mg) and 4 mol/L hydrogen chloride/ethyl acetate solution (1.0 mL)was stirred at room temperature overnight, and the solvent wasevaporated under reduced pressure to give the title compound (33.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.29-1.41 (1H, m), 1.44-1.64 (2H, m), 1.72(1H, brs), 2.01 (3H, d, J=12.49), 2.63 (3H, s), 2.76-3.08 (7H, m),3.17-3.35 (3H, m), 3.42-3.56 (2H, m), 7.51 (1H, s), 8.46 (1H, d,J=1.14), 9.36-9.73 (2H, m), 9.96-12.92 (2H, m).

The compounds of Examples 61 to 66 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 614-(trans-2-(cyclobutylamino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride Example 624-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride Example 634-(trans-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride Example 644-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride Example 655-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-2-methylthiophene-3-carboxamidehydrochloride Example 66N-(4,4-difluorocyclohexyl)-2-methyl-5-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidehydrochloride Example 67N-(4,4-difluorocyclohexyl)-2-methyl-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamidehydrochloride

To a mixture of5-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)-2-methylthiophene-3-carboxamidehydrochloride (30.0 mg), sodium hydrogen carbonate (10.8 mg), THF (1.5mL) and methanol (1.5 mL) was added dihydro-2H-pyran-4(3H)-one (9.48μL). Under a nitrogen atmosphere, the reaction mixture was stirred at60° C. for 1.5 hr and at room temperature for 30 min, and sodiumborohydride (4.85 mg) was added under ice-cooling. The reaction mixturewas stirred at room temperature for 1 hr, and diluted with ethylacetate. Water and saturated aqueous sodium hydrogen carbonate solutionwere added, and the mixture was extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate/methanol). To the obtained fraction wasadded 4 mol/L hydrogen chloride/ethyl acetate solution, and the mixturewas stirred overnight. The precipitated solid was collected byfiltration and washed with ethyl acetate to give the title compound(15.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.22-1.36 (1H, m), 1.49-1.75 (5H, m),1.78-2.09 (9H, m), 2.53 (3H, s), 2.64 (1H, brs), 2.89 (1H, brs), 3.45(1H, brs), 3.93 (3H, d, J=10.98 Hz), 7.06 (1H, s), 7.83 (1H, d, J=7.95Hz), 9.50 (2H, brs).

Example 685-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

Example 695-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride

To a mixture of5-(trans-2-aminocyclopropyl)-2-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamidedihydrochloride (30.0 mg), sodium hydrogen carbonate (17.2 mg), THF (1.5mL) and methanol (1.5 mL) was added cyclopropanecarbaldehyde (7.32 μL).Under a nitrogen atmosphere, the reaction mixture was stirred at 60° C.for 1.5 hr and at room temperature for 30 min. Sodium borohydride (4.63mg) was added under ice-cooling, and the reaction mixture was stirred atroom temperature for 1 hr and diluted with ethyl acetate. Water andsaturated aqueous sodium hydrogen carbonate solution were added, and themixture was extracted with ethyl acetate. The extract was successivelywashed with water and saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate/methanol). To the obtained fraction was added 4 mol/L hydrogenchloride/ethyl acetate solution, and the mixture was stirred overnight.The precipitated solid was collected by filtration and washed with ethylacetate to give the title compound (22.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.35-0.45 (2H, m), 0.55-0.65 (2H, m),1.03-1.20 (1H, m), 1.24-1.36 (1H, m), 1.59-1.70 (1H, m), 2.60-2.75 (8H,m), 2.86-3.02 (3H, m), 7.47 (1H, s), 9.51 (2H, d, J=4.54 Hz).

Example 70

2-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

Example 715-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride A)((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methanamine(1R,2R)-2-(4-bromothiophen-2-yl)cyclopropanecarboxylate

((1R,4aS,10aR)-7-Isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methanamine(1.040 g) was dissolved in methanol (3.2 mL) and diisopropyl ether (15.7mL) at 40° C., and trans-2-(4-bromothiophen-2-yl)cyclopropanecarboxylicacid (900 mg) was added. The reaction mixture was stirred for 5 min atthe same temperature, and methanol (8 mL) was added. The reactionmixture was heated to 53° C. to dissolve the precipitate. The reactionmixture was cooled to 46° C. and stirred at 46-47° C. for 2 hr. Thereaction mixture was slowly cooled to room temperature (28° C.) andstirred overnight. The precipitate was collected by filtration, and theobtained solid was washed with a mixed solvent of ethyl acetate/hexane(1/5=ethyl acetate/hexane (v/v), 4 mL) to give the title compound (594mg, 95.7% d.e.).

MS: [M−H—(C₂₀H₃₁N)]⁻ 245.0.

Column: CHIROBIOTIC R 4.6 mmID×250 mmL

Eluent solvent: Methanol/TEA/AA=1000/3/1 (v/v/v)

Flow rate: 1.0 mL/min

Retention time: 4.4 min.

Temperature: 300° C.

Detection: UV 254 nm

Concentration: 0.5 mg/mL

Injection volume: 0.010 mL

B)((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methanamine(1R,2R)-2-(4-bromothiophen-2-yl)cyclopropanecarboxylate

((1R,4aS,10aR)-7-Isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methanamine(1R,2R)-2-(4-bromothiophen-2-yl)cyclopropanecarboxylate (290 mg, 95.7%d.e.) was dissolved in ethanol (3.77 mL) and diisopropyl ether (1.45 mL)at 62° C., and diisopropyl ether (8.12 mL) was further added dropwise at62° C. The mixture was cooled to 46° C. and stirred at 45-47° C. for 2hr. The mixture was slowly cooled to room temperature (28° C.) andstirred overnight. Furthermore, the mixture was stirred at 0° C. for 1hr. The precipitate was collected by filtration, and the obtained solidwas washed with ethyl acetate/hexane (1/5=ethyl acetate/hexane (v/v), 2mL) to give the title compound (246 mg, 99.6% d.e.).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, s), 1.00-1.76 (19H, m), 2.21-2.38(2H, m), 2.39-2.47 (2H, m), 2.71-2.87 (2H, m), 3.38-3.50 (2H, m),6.81-6.86 (1H, m), 6.88-6.92 (1H, m), 6.92-6.98 (1H, m), 7.10-7.19 (1H,m), 7.40 (1H, d, J=1.5 Hz).

Column: CHIROBIOTIC R 4.6 mmID×250 mmL

Eluent solvent: Methanol/TEA/AA=1000/3/1 (v/v/v)

Flow rate: 1.0 mL/min

Retention time: 4.3 min.

Temperature: 300° C.

Detection: UV 254 nm

Concentration: 0.5 mg/mL

Injection volume: 0.010 mL

C) (1R,2R)-2-(4-bromothiophen-2-yl)cyclopropanecarboxylic acid

To a suspension of((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methanamine(1R,2R)-2-(4-bromothiophen-2-yl)cyclopropanecarboxylate (26.8 g) inethyl acetate (300 mL) were added 1 mol/L aqueous sodium hydroxidesolution (60.4 mL) and water (200 mL) at room temperature, and themixture was stirred at room temperature for 5 min. The aqueous layer wasseparated and washed with ethyl acetate (200 mL, twice). To the aqueouslayer was added 2 mol/L hydrochloric acid (35.2 mL) under ice-cooling at0° C. to adjust the mixture from pH 2 to pH 3, and the mixture wasextracted with ethyl acetate (100 mL, twice). The organic layer wasseparated, and the extract was washed with saturated brine, and driedover magnesium sulfate. The solvent was evaporated under reducedpressure to give the title compound (11.7 g).

¹H NMR (300 MHz, CDCl₃) δ 1.39 (1H, ddd, J=8.5, 6.4, 4.7 Hz), 1.64-1.73(1H, m), 1.90-1.98 (1H, m), 2.66-2.78 (1H, m), 6.75 (1H, dd, J=1.5, 0.8Hz), 7.02 (1H, d, J=1.5 Hz).

D) tert-butyl ((1R,2R)-2-(4-bromothiophen-2-yl)cyclopropyl)carbamate

To a solution of (1R,2R)-2-(4-bromothiophen-2-yl)cyclopropanecarboxylicacid (15 g) and tert-butyl alcohol (150 mL) were added triethylamine(10.15 mL) and diphenylphosphoryl azide (13.07 mL) at room temperature,and the mixture was stirred at room temperature for 1 hr, and then at80° C. overnight. The reaction mixture was cooled to room temperature,saturated aqueous sodium hydrogen carbonate solution was added, and themixture was extracted with ethyl acetate. The organic layer wasseparated, successively washed with water and saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (14.6 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.04-1.24 (2H, m), 1.38 (9H, s), 2.07 (1H,ddd, J=9.18, 6.15, 3.22 Hz), 2.61 (1H, brs), 6.80 (1H, d, J=0.76 Hz),7.27 (1H, brs), 7.38 (1H, d, J=1.51 Hz).

E) methyl5-((1R,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylate

To a solution of tert-butyl((1R,2R)-2-(4-bromothiophen-2-yl)cyclopropyl)carbamate (7.2 g) inmethanol (180 mL) were added triethylamine (6.31 mL) anddichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (828 mg) at roomtemperature, and the mixture was stirred at 90° C. for 6 hr under acarbon monoxide atmosphere (3 atm). The reaction mixture was filteredthrough celite and washed with methanol. The filtrate was concentratedunder reduced pressure, water was added to the residue, and the mixturewas extracted with ethyl acetate. The contaminants in the organic layerwere removed by filtration, and the filtrate was concentrated underreduced pressure to give residue A.

To a solution of tert-butyl((1R,2R)-2-(4-bromothiophen-2-yl)cyclopropyl)carbamate (7.2 g) inmethanol (180 mL) were added triethylamine (6.31 mL) anddichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (828 mg) at roomtemperature, and the mixture was stirred at 90° C. for 6 hr under acarbon monoxide atmosphere (3 atm). The reaction mixture was filteredthrough celite, and washed with methanol. The filtrate was concentratedunder reduced pressure, water was added to the residue, and the mixturewas extracted with ethyl acetate. The contaminants in the organic layerwere removed by filtration, and the filtrate was concentrated underreduced pressure to give residue B.

The residues A and B were combined and purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (11.1g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.05-1.25 (2H, m), 1.35-1.42 (9H, m), 2.08(1H, ddd, J=9.18, 6.34, 3.03 Hz), 2.60 (1H, brs), 3.76 (3H, s), 7.12(1H, d, J=0.76 Hz), 7.28 (1H, brs), 8.07 (1H, d, J=1.51 Hz).

F)5-((1R,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-3-carboxylicacid

By a method similar to that of Example 38, step C, the title compoundwas obtained.

G) tert-butyl((1R,2R)-2-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-2-yl)cyclopropyl)carbamate

By a method similar to that of Example 42, step A, the title compoundwas obtained.

H)5-((1R,2R)-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidedihydrochloride

By a method similar to that of Example 42, step B, the title compoundwas obtained.

I)5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride

To a mixture of5-((1R,2R)-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidedihydrochloride (1.54 g), triethylamine (2.12 mL), THF (20 mL) andmethanol (20 mL) was added cyclopropanecarbaldehyde (0.428 g) at roomtemperature. The reaction mixture was stirred at room temperature for 2hr, and sodium borohydride (0.231 g) was added at 0° C. The reactionmixture was stirred at 0° C. for 10 min and added to water. The methanoland tetrahydrofuran were evaporated under reduced pressure, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate/methanol). To theobtained fraction was added 4 mol/L hydrogen chloride/ethyl acetatesolution and the mixture was concentrated under reduced pressure. Theobtained residue was crystallized from ethanol/heptane to give the titlecompound (1.04 g).

¹H NMR (300 MHz, DMSO-d₆) δ 0.33-0.43 (2H, m), 0.51-0.64 (2H, m),0.99-1.15 (1H, m), 1.24-1.37 (1H, m), 1.42-1.65 (3H, m), 1.67-1.78 (2H,m), 2.64-2.75 (1H, m), 2.90-3.04 (3H, m), 3.32-3.42 (2H, m), 3.79-4.00(3H, m), 7.28 (1H, s), 7.95 (1H, d, J=1.5 Hz), 8.05 (1H, d, J=8.0 Hz),9.25 (2H, brs).

The compounds of Examples 72 to 80 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 72N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-((1S,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamidehydrochloride Example 734-((1R,2S)-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride Example 74N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-((1R,2S)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamidehydrochloride Example 754-((1R,2S)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride Example 764-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride Example 774-((1S,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride Example 784-((1S,2R)-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride Example 794-((1R,2S)-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride Example 805-((1R,2R)-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride Example 81N-(5-methyl-1,2-oxazol-3-yl)-5-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidehydrochloride A) tert-butyl((1R,2R)-2-(4-((5-methylisoxazol-3-yl)carbamoyl)thiophen-2-yl)cyclopropyl)((tetrahydro-2H-pyran-4-yl)methyl)carbamate

To a mixture of 5-((1R,2R)-2-((tert-butoxycarbonyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)cyclopropyl)thiophene-3-carboxylicacid (50.0 mg) and THF (2 mL) was added oxalyl chloride (0.014 mL) at 0°C., and the mixture was stirred at 0° C. for 1 hr. The solvent wasevaporated under reduced pressure to give an acid chloride intermediate.

To a mixture of 5-methylisoxazol-3-amine (19.3 mg), DMAP (8.01 mg) andpyridine (2 mL) was added a mixture of the aforementioned acid chlorideand THF (1.5 mL) at 60° C., and the mixture was stirred at 60° C. for 2hr. The reaction mixture was neutralized with saturated aqueous sodiumhydrogen carbonate solution, and extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (17.2mg).

MS: [M-Boc+H]⁺ 362.3.

B)N-(5-methyl-1,2-oxazol-3-yl)-5-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidehydrochloride

By a method similar to that of Example 1, step H, the title compound wasobtained.

Example 824-((1S,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride A) (R)-2-amino-3-phenylpropan-1-ol(1R,2R)-2-(5-bromothiophen-3-yl)cyclopropanecarboxylate

trans-2-(5-Bromothiophen-3-yl)cyclopropanecarboxylic acid (47.8 g) and(R)-2-amino-3-phenylpropan-1-ol (29.2 g) were dissolved in ethanol (480mL) at 57° C., diisopropyl ether (480 mL) was added, and the mixture wascooled to 53° C. The reaction mixture was stirred at 53° C. for 1 hr,cooled to room temperature, and stirred overnight. The reaction mixturewas cooled to 0° C. and stirred for 1 hr. The precipitate was collectedby filtration, and washed with a mixed solvent of ethyl acetate/hexane(1/2=ethyl acetate/hexane (v/v)) to give the title compound (32.6g, >99% d.e.).

MS: [M−H—(C₉H₁₃NO)]⁻ 246.8.

B) (R)-2-amino-3-phenylpropan-1-ol(1R,2R)-2-(5-bromothiophen-3-yl)cyclopropanecarboxylate

(R)-2-Amino-3-phenylpropan-1-ol(1R,2R)-2-(5-bromothiophen-3-yl)cyclopropanecarboxylate (32.5 g) wasdissolved in ethanol (430 mL) at 60° C., diisopropyl ether (850 mL) wasadded, and the mixture was cooled to 55° C. The reaction mixture wasstirred at 55° C. for 1 hr, cooled to room temperature, and stirredovernight. The reaction mixture was cooled to 0° C., stirred for 1 hr,and the precipitate was collected by filtration and washed with a mixedsolvent of ethyl acetate/hexane (1/2=ethyl acetate/hexane (v/v)) to givethe title compound (27.5 g, >99% d.e.).

MS: [M−H—(C₉H₁₃NO)]⁻ 246.8.

C) (1R,2R)-2-(5-bromothiophen-3-yl)cyclopropanecarboxylic acid

To a mixture of (R)-2-amino-3-phenylpropan-1-ol(1R,2R)-2-(5-bromothiophen-3-yl)cyclopropanecarboxylate (26.0 g) andethyl acetate was added 1 mol/L aqueous hydrochloric acid solution, andthe mixture was extracted with ethyl acetate. The extract wassuccessively washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. Toluene was added to the residue, and the mixture wasconcentrated under reduced pressure to give the title compound (16.1 g).

MS: [M−H]⁻ 246.8.

D) tert-butyl ((1R,2S)-2-(5-bromothiophen-3-yl)cyclopropyl)carbamate

To a mixture of (1R,2R)-2-(5-bromothiophen-3-yl)cyclopropanecarboxylicacid (16.0 g) and tert-butyl alcohol (200 mL) were added triethylamine(10.8 mL) and diphenylphosphoryl azide (16.7 mL) at room temperature,and the mixture was stirred at room temperature for 2 hr and at 80° C.overnight. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was successively washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (18.1 g).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91-1.11 (2H, m), 1.37 (9H, s), 1.87 (1H,ddd, J=9.28, 6.25, 3.41 Hz), 2.56 (1H, s), 7.00 (1H, d, J=1.89 Hz), 7.12(1H, d, J=1.89 Hz), 7.18 (1H, brs).

E) methyl4-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate

To a mixture of tert-butyl((1R,2S)-2-(5-bromothiophen-3-yl)cyclopropyl)carbamate (9.00 g) andmethanol (200 mL) were added triethylamine (7.88 mL) and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.04 g),and the mixture was heated at 90° C. for 6 hr under a carbon monoxideatmosphere (3 atm). The insoluble material was filtered off by celiteand washed with methanol, and the filtrate was concentrated underreduced pressure and extracted with ethyl acetate and water. The extractwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to giveresidue A.

To a mixture of tert-butyl((1R,2S)-2-(5-bromothiophen-3-yl)cyclopropyl)carbamate (9.00 g) andmethanol (200 mL) were added triethylamine (7.88 mL) and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.04 g),and the mixture was stirred at 90° C. for 6 hr under a carbon monoxideatmosphere (3 atm). The insoluble material was filtered off by celiteand washed with methanol, and the filtrate was concentrated underreduced pressure and extracted with ethyl acetate and water. The extractand the residues A were combined, washed with 5% ammonia water (twice),N-acetyl-L-cysteine aqueous solution (twice), water and saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (15.2g).

MS: [M-Boc+2H]⁺ 198.1.

F)4-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylicacid

To a solution of methyl4-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate(15.2 g) in THF (50 mL)/methanol (50 mL) was added 2 mol/L aqueoussodium hydroxide solution (63.9 mL) at 0° C., and the mixture wasstirred at room temperature overnight. The reaction mixture wasacidified with 1 mol/L hydrochloric acid at 0° C., and extracted withethyl acetate. The extract was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained residue was washed with diisopropylether to give the title compound (13.4 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.00-1.11 (2H, m), 1.34-1.42 (9H, m), 1.92(1H, ddd, J=9.09, 6.25, 3.22 Hz), 2.54-2.66 (1H, m), 7.21 (1H, br. s.),7.42 (1H, d, J=1.14 Hz), 7.50 (1H, d, J=1.51 Hz), 12.99 (1H, brs).

G) tert-butyl((1R,2S)-2-(5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate

To a solution of4-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylicacid (13.3 g) in DMF (200 mL) were added5-methyl-1,3,4-thiadiazol-2-amine (6.49 g), triethylamine (13.08 mL) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (21.42 g), and the mixture was stirred at roomtemperature overnight. To the reaction mixture were added water andethyl acetate, and the precipitate was collected by filtration andwashed with ethyl acetate to give the title compound (12.1 g). Thefiltrate was extracted with ethyl acetate. The organic layer wassuccessively washed with 0.1 mol/L hydrochloric acid, saturated aqueoussodium hydrogen carbonate solution, water and saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.To the residue was added ethyl acetate, and the precipitate wascollected by filtration. The obtained solid was washed with ethylacetate to give the title compound (2.86 g).

MS: [M+H]⁺ 381.1.

H)4-((1S,2R)-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride

To a suspension of tert-butyl((1R,2S)-2-(5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate(1.67 g) in ethyl acetate (10 mL) and methanol (10 mL) was added 4 mol/Lhydrogen chloride/ethyl acetate solution (10.97 mL) at 0° C., and themixture was stirred at room temperature overnight. The precipitatedsolid was collected by filtration, and washed with ethyl acetate to givethe title compound (1.55 g).

MS: [M+H-(2HCl)]⁺ 281.0.

I)4-((1S,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride

To a mixture of4-((1S,2R)-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride (1.00 g), sodium hydrogen carbonate (549 mg), THF (15mL) and methanol (15 mL) was added cyclopropanecarbaldehyde (254 μL).Under a nitrogen atmosphere, the reaction mixture was stirred at 60° C.for 1.5 hr and at room temperature for 30 min. Sodium borohydride (161mg) was added under ice-cooling, and the reaction mixture was stirred atroom temperature for 1 hr. The reaction mixture was diluted with ethylacetate, water and saturated aqueous sodium hydrogen carbonate solutionwere added, and the mixture was extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (ethyl acetate/methanol). To the obtained fractionwas added 4 mol/L hydrogen chloride/ethyl acetate solution, and themixture was stirred overnight and concentrated under reduced pressure.The residue was crystallized from methanol/diisopropyl ether to give thetitle compound (723 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.33-0.42 (2H, m), 0.54-0.65 (2H, m),1.01-1.17 (1H, m), 1.20-1.32 (1H, m), 1.53-1.66 (1H, m), 2.56-2.65 (4H,m), 2.86-3.02 (3H, m), 7.75 (1H, s), 8.07 (1H, brs), 9.26-9.56 (2H, m).

Example 834-((1R,2S)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

Example 844-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride

To a mixture of(1S,2R)-4-(2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride (3.36 g), THF (30 mL) and methanol (30 mL) was addedtriethylamine (3.31 mL), triethyl orthoformate (2.10 mL) andcyclobutanone (0.856 mL) at room temperature, and the mixture wasstirred at room temperature overnight. Sodium borohydride (540 mg) wasadded under ice-cooling, and the reaction mixture was stirred at roomtemperature for 1 hr. The reaction mixture was diluted with ethylacetate, water and saturated aqueous sodium hydrogen carbonate solutionwere added, and the mixture was extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (ethyl acetate/methanol). To the obtained fractionwas added 4 mol/L hydrogen chloride/ethyl acetate solution, and themixture was stirred overnight and concentrated under reduced pressure.The residue was crystallized from ethanol/water/ethyl acetate to givethe title compound (2.17 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.18-1.29 (1H, m), 1.48-1.60 (1H, m),1.72-1.89 (2H, m), 2.12-2.39 (4H, m), 2.54-2.67 (4H, m), 2.74-2.86 (1H,m), 3.74-3.92 (1H, m), 7.74 (1H, d, J=1.14 Hz), 8.06 (1H, s), 9.79 (2H,brs).

The compounds of Examples 85 to 92 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 854-((1R,2S)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride Example 86N-(1-ethyl-1H-pyrazol-4-yl)-5-((1R,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamidedihydrochloride Example 874-((1S,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride Example 884-((1R,2S)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride Example 894-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride Example 904-((1R,2S)-2-(cyclobutylamino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride Example 915-((1R,2R)-2-((1-acetylpiperidin-4-yl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride Example 925-((1R,2R)-2-((1-(cyclopropylcarbonyl)piperidin-4-yl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamidehydrochloride Example 93N-(4,4-difluorocyclohexyl)-5-methyl-4-((1S,2R)-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-2-carboxamidefumarate A)4-((1S,2R)-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamidehydrochloride

4-((1S,2R)-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid (50 mg), 4,4-difluorocyclohexanamine (27.3 mg) and triethylamine(0.094 mL) were dissolved in DMF (1 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (77 mg) was added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and saturated brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The obtained residue(70.5 mg) and 4 mol/L hydrogen chloride/ethyl acetate solution (4.0 mL)were stirred at room temperature overnight. The precipitated solid wascollected by filtration and washed with ethyl acetate to give the titlecompound (51 mg).

MS: [M-HCl+H]⁺ 315.1.

B)N-(4,4-difluorocyclohexyl)-5-methyl-4-((1S,2R)-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-2-carboxamidefumarate

To a mixture of4-((1S,2R)-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamidehydrochloride (40.0 mg), borane-2-picoline complex (36.7 mg), methanol(2.0 mL) and acetic acid (0.2 mL) was added dihydro-2H-pyran-4(3H)-one(17.1 mg) at room temperature. The reaction mixture was stirred at roomtemperature for 18 hr, and saturated aqueous sodium hydrogen carbonatesolution was added at 0° C. The mixture was extracted with ethylacetate, and the extract was successively washed with water andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane), the obtainedresidue was dissolved in ethyl acetate, and a solution of fumaric acid(9.3 mg) in ethanol was added at room temperature. The reaction mixturewas stirred at room temperature for 30 min, and the solvent wasevaporated under reduced pressure to give the title compound (40.0 mg).

¹H NMR (300 MHz, DMSO-d6) δ 0.76-0.91 (1H, m), 0.95-1.04 (1H, m),1.21-1.40 (2H, m), 1.48-1.66 (2H, m), 1.69-2.11 (9H, m), 2.26-2.34 (1H,m), 2.40 (3H, s), 2.75-2.87 (1H, m), 3.23-3.34 (2H, m), 3.76-3.96 (3H,m), 6.60 (2H, s), 7.21 (1H, s), 7.94-8.05 (1H, m).

Example 94N-(4,4-difluorocyclohexyl)-5-methyl-4-((1R,2S)-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-2-carboxamidefumarate

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

Example 954-((1S,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidefumarate A)4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide

4-((1S,2R)-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid (150 mg), 5-methyl-1,3,4-thiadiazol-2-amine (69.7 mg) andtriethylamine (0.281 mL) were dissolved in DMF (5 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (230 mg) was added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe precipitate was collected by filtration to give solid A. Thefiltrate was extracted with ethyl acetate. The organic layer wassuccessively washed with water and saturated brine, dried over magnesiumsulfate, and concentrated under reduced pressure to give solid B. Thesolid (197 mg) combined with the obtained solids A and B, and 4 mol/Lhydrogen chloride/ethyl acetate solution (4 mL) were stirred at roomtemperature overnight. The precipitated solid was collected byfiltration, and washed with ethyl acetate to give the title compound(120 mg).

MS: [M-HCl+H]⁺ 295.1.

B)4-((1S,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidefumarate

To a mixture of4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidehydrochloride (40.0 mg), triethylamine (22.0 mg), THF (1.0 mL) andmethanol (1.0 mL) was added cyclopropanecarbaldehyde (11.8 mg) at roomtemperature. The reaction mixture was stirred at 50° C. for 1.5 hr, andstirred at room temperature for 1 hr. Sodium borohydride (8.2 mg) wasadded at 0° C., the reaction mixture was stirred at 0° C. for 30 min,and ethyl acetate, water and saturated aqueous sodium hydrogen carbonatesolution were added to the reaction mixture. The mixture was extractedwith ethyl acetate/THF, and the extract was washed with saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate), the obtained residue wassuspended in ethyl acetate, and a solution of fumaric acid (8.4 mg) inethanol was added at room temperature. The reaction mixture was stirredat room temperature for 30 min, and the solid was collected byfiltration to give the title compound (28.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.10-0.21 (2H, m), 0.37-0.49 (2H, m),0.85-1.00 (2H, m), 1.04-1.16 (1H, m), 1.80-1.92 (1H, m), 2.40-2.46 (1H,m), 2.48 (3H, s), 2.56-2.60 (2H, m), 2.61 (3H, s), 6.58 (2H, s), 7.76(1H, s).

Example 964-((1R,2S)-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidefumarate

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

Example 975-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-((1S,2R)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamidehydrochloride

To a mixture of4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidehydrochloride (40.0 mg), triethylamine (22.0 mg), THF (1.0 mL) andmethanol (1.0 mL) was added tetrahydro-2H-pyran-4-carbaldehyde (18.6 mg)at room temperature. The reaction mixture was stirred at roomtemperature overnight, sodium borohydride (8.2 mg) was added at 0° C.,and the reaction mixture was stirred at 0° C. for 10 min. To thereaction mixture were added ethyl acetate and water, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography(methanol/ethyl acetate), and to the obtained fraction was added 4 mol/Lhydrogen chloride/ethyl acetate solution. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue wascrystallized from ethanol/heptane to give the title compound (31.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.14-1.35 (4H, m), 1.52-1.63 (1H, m),1.64-1.76 (2H, m), 1.86-2.06 (1H, m), 2.53 (3H, s), 2.62 (3H, s),2.86-3.09 (3H, m), 3.21-3.30 (2H, m), 3.79-3.95 (2H, m), 7.70-8.03 (1H,m), 8.94-9.41 (2H, m), 12.34-12.97 (1H, m).

Example 985-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-((1R,2S)-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamidehydrochloride

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

Example 994-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidehydrochloride

To a mixture of4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride (40.0 mg), triethylamine (22.0 mg), trimethylorthoformate (17.3 mg), methanol (1.0 mL) and THF (1.0 mL) was addedcyclobutanone (11.8 mg) at room temperature, and the mixture was stirredat room temperature for 3 hr. Sodium borohydride (8.2 mg) was addedunder ice-cooling, the reaction mixture was stirred for 30 min, andethyl acetate and saturated aqueous sodium hydrogen carbonate solutionwere added. The mixture was extracted with ethyl acetate/THF, and theextract was washed with saturated brine. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate/methanol), and to the obtained fractionwas added 4 mol/L hydrogen chloride/ethyl acetate solution. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was washed with ethyl acetate to give the title compound (18.0mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.12-1.24 (1H, m), 1.45-1.57 (1H, m),1.74-1.92 (2H, m), 2.17-2.31 (4H, m), 2.34-2.46 (1H, m), 2.62 (3H, s),2.71-2.86 (1H, m), 3.31 (3H, s), 3.76-3.94 (1H, m), 7.70-7.91 (1H, m),9.06-9.71 (2H, m), 12.20-13.03 (1H, m).

Example 1004-((1R,2S)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidehydrochloride

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

Example 1014-((4-((((1R,2R)-2-(4-((4,4-difluorocyclohexyl)carbamoyl)-2-thienyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoicacid dihydrochloride

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

Example 1024-((1S,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride

To a mixture of4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride (35.0 mg), sodium hydrogen carbonate (21.0 mg), THF (1.5mL) and methanol (1.5 mL) was added cyclopropanecarbaldehyde (8.99 μL).Under a nitrogen atmosphere, the reaction mixture was stirred at 60° C.for 1.5 hr and at room temperature for 30 min, sodium borohydride (5.69mg) was added under ice-cooling, and the reaction mixture was stirred atroom temperature for 1 hr. The reaction mixture was diluted with ethylacetate, water and saturated aqueous sodium hydrogen carbonate solutionwere added, and the mixture was extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate/methanol), and to the obtained fractionwas added 4 mol/L hydrogen chloride/ethyl acetate solution. The mixturewas stirred overnight, and the precipitated solid was collected byfiltration, and washed with ethyl acetate to give the title compound(32.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.33-0.45 (2H, m), 0.50-0.66 (2H, m),1.00-1.26 (2H, m), 1.50-1.65 (1H, m), 2.49 (3H, s), 2.82-3.05 (3H, m),3.80 (3H, s), 7.49-7.58 (2H, m), 7.92 (1H, s), 9.41 (2H, brs), 10.34(1H, s).

MS: [M-2HCl+H]⁺ 331.2.

Example 1034-((1R,2S)-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

Example 1044-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride

To a mixture of4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride (35.0 mg), sodium hydrogen carbonate (21.0 mg), THF (1.5mL) and methanol (1.5 mL) was added cyclobutanone (9.01 μL). Under anitrogen atmosphere, the reaction mixture was stirred at 60° C. for 1.5hr and at room temperature for 30 min, sodium borohydride (5.69 mg) wasadded under ice-cooling, and the reaction mixture was stirred at roomtemperature for 1 hr. The reaction mixture was diluted with ethylacetate, water and saturated aqueous sodium hydrogen carbonate solutionwere added, and the mixture was extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate/methanol), and to the obtained fractionwas added 4 mol/L hydrogen chloride/ethyl acetate solution. The mixturewas stirred overnight, and the precipitated solid was collected byfiltration, and washed with ethyl acetate to give the title compound(29.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.10-1.24 (1H, m), 1.49-1.60 (1H, m),1.72-1.89 (2H, m), 2.15-2.35 (4H, m), 2.39-2.48 (4H, m), 2.73-2.84 (1H,m), 3.76-3.91 (4H, m), 7.50-7.56 (2H, m), 7.92 (1H, s), 9.72 (2H, d,J=3.79 Hz), 10.33 (1H, s).

The compounds of Examples 105 to 107 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 1054-((1R,2S)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride [Optical Isomer, Compound Derived from methyl4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate(Optical Isomer, Retention Time Long)] Example 1064-((1S,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride Example 1074-((1R,2S)-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride Example 1084-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride A) tert-butyl((1R,2S)-2-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate

4-((1S,2R)-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid (100 mg), tetrahydro-2H-pyran-4-amine (0.042 mL) and triethylamine(0.117 mL) were dissolved in DMF (5 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (153 mg) was added, and the mixture was stirred atroom temperature overnight. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate, and purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (114 mg).

MS: [M-HCl+H]⁺ 381.3.

B)4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride

To a solution of tert-butyl((1R,2S)-2-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate(110 mg) in ethyl acetate (3 mL) was added 4 mol/L hydrogenchloride/ethyl acetate solution (0.723 mL), and the mixture was stirredat room temperature overnight. The precipitated solid was collected byfiltration and washed with ethyl acetate to give the title compound (92mg).

MS: [M-HCl+H]⁺ 281.2.

C)4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride

To a mixture of4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride (35.0 mg), sodium hydrogen carbonate (13.9 mg), THF (1.5mL) and methanol (1.5 mL) was added cyclobutanone (9.94 μL). Under anitrogen atmosphere, the reaction mixture was stirred at 60° C. for 1.5hr and at room temperature for 30 min, sodium borohydride (6.27 mg) wasadded under ice-cooling, and the reaction mixture was stirred at roomtemperature for 1 hr. The reaction mixture was diluted with ethylacetate, water and saturated aqueous sodium hydrogen carbonate solutionwere added, and the mixture was extracted with ethyl acetate. Theextract was successively washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate/methanol), and to the obtained fractionwas added 4 mol/L hydrogen chloride/ethyl acetate solution. The mixturewas stirred overnight, and the precipitated solid was collected byfiltration and washed with ethyl acetate to give the title compound(29.7 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.10-1.19 (1H, m), 1.43-1.59 (3H, m),1.67-1.87 (4H, m), 2.14-2.30 (4H, m), 2.34-2.43 (1H, m), 2.44 (3H, s),2.69-2.81 (1H, m), 3.35-3.40 (1H, m), 3.76-3.97 (4H, m), 7.30-7.39 (1H,m), 8.08 (1H, d, J=7.95 Hz), 9.56 (2H, brs).

Example 1094-((1R,2S)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride

The title compound could be produced according to the production methodsdescribed in the present specification, a method shown in the Examples,or a method analogous thereto.

The compounds of Examples 110 and 111 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 1104-((((1R,2R)-2-(4-((4,4-difluorocyclohexyl)carbamoyl)-2-thienyl)cyclopropyl)amino)methyl)benzoicacid Example 1115-((1R,2R)-2-(((5-amino-1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamideExample 1125-((1R,2R)-2-((cyclobutylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide

To a mixture of5-((1R,2R)-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidedihydrochloride (40 mg), triethylamine (0.055 mL), THF (1 mL) andmethanol (1 mL) was added cyclobutanecarbaldehyde (13.33 mg) at roomtemperature. The reaction mixture was stirred at room temperature for 5min, and sodium borohydride (7.5 mg) was added at 0° C. The reactionmixture was stirred at room temperature for 10 min. To the reactionmixture were added water, ethyl acetate and saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methanol), and to the obtained fractionwas added 4 mol/L hydrogen chloride/ethyl acetate solution. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was washed with ethyl acetate to give the title compound (31mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.21-1.35 (1H, m), 1.44-1.65 (3H, m), 1.82(6H, d, J=7.2 Hz), 1.98-2.14 (2H, m), 2.57-2.79 (2H, m), 2.88-2.98 (1H,m), 3.06-3.16 (2H, m), 3.35-3.42 (2H, m), 3.80-4.00 (3H, m), 7.28 (1H,s), 7.95 (1H, d, J=1.5 Hz), 8.06 (1H, d, J=7.6 Hz), 9.01-9.34 (2H, m).

Example 1135-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidemalate

To a suspension of L-(−)-malic acid (50.2 mg, 0.37 mmol) in ethylacetate (2 mL) was added a solution of5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide(120 mg, 0.37 mmol) in ethanol (1 mL) at 60° C. The reaction mixture wasstirred at room temperature for 1 hr, and concentrated under reducedpressure. To the residue were added ethyl acetate (2 mL) and ethanol(0.5 mL), and ethyl acetate (2 mL) was further added. The precipitatewas collected by filtration to give the title compound (106 mg). Theobtained title compound (106 mg) was recrystallized from ethanol (0.3mL) and ethyl acetate (1.2 mL) to give the title compound (65.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.12-0.25 (2H, m), 0.37-0.54 (2H, m),0.82-1.12 (2H, m), 1.23 (1H, dt, J=9.6, 4.9 Hz), 1.41-1.62 (2H, m), 1.72(2H, dd, J=12.9, 2.3 Hz), 2.14-2.29 (1H, m), 2.33-2.43 (1H, m),2.52-2.73 (4H, m), 3.17-3.46 (2H, m), 3.81-4.00 (3H, m), 4.06 (1H, dd,J=7.6, 6.1 Hz), 7.18 (1H, d, J=0.8 Hz), 7.84 (1H, d, J=1.1 Hz), 7.99(1H, d, J=8.0 Hz).

Example 114 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidesuccinate

To a solution of succinic acid (36.9 mg, 0.31 mmol) in ethanol (3 mL)was added 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide (100mg, 0.31 mmol) at 60° C. The reaction mixture was stirred at roomtemperature for 1 hr and concentrated under reduced pressure. To theresidue were added ethyl acetate (2 mL) and ethanol (0.5 mL), and ethylacetate (2 mL) was further added. The precipitate was collected byfiltration to give the title compound (105 mg). The obtained titlecompound (105 mg) was recrystallized from ethanol (0.8 mL) and ethylacetate (1.2 mL) to give the title compound (62.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.06-0.19 (2H, m), 0.34-0.49 (2H, m),0.78-1.15 (3H, m), 1.41-1.61 (2H, m), 1.64-1.78 (2H, m), 1.97-2.07 (1H,m), 2.32-2.43 (5H, m), 2.50-2.54 (2H, m), 3.30-3.52 (2H, m), 3.75-4.01(3H, m), 7.13 (1H, d, J=0.8 Hz), 7.79 (1H, d, J=1.1 Hz), 7.97 (1H, d,J=8.0 Hz).

Example 115 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidefumarate

To a solution of fumaric acid (42.7 mg, 0.37 mmol) in ethanol (1 mL) wasadded a solution of5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide(118 mg, 0.37 mmol) in ethyl acetate (3 mL) at 60° C. To the reactionmixture was added ethyl acetate (2 mL), the mixture was stirred at roomtemperature, and the precipitate was collected by filtration to give thetitle compound (122 mg). The obtained title compound (122 mg) wasrecrystallized from ethanol (1.08 mL) and ethyl acetate (1.8 mL) to givethe title compound (85 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.06-0.17 (2H, m), 0.36-0.48 (2H, m),0.82-1.18 (3H, m), 1.52 (2H, qd, J=11.9, 4.4 Hz), 1.66-1.80 (2H, m),2.00-2.12 (1H, m), 2.35-2.44 (1H, m), 2.50-2.57 (2H, m), 3.36 (2H, td,J=11.5, 1.9 Hz), 3.75-4.01 (3H, m), 6.59 (2H, s), 7.13 (1H, s), 7.80(1H, d, J=1.5 Hz), 7.98 (1H, d, J=8.0 Hz).

Example 1164-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidephosphate

To a mixture of4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide(100 mg) and ethanol (4 mL) was added 1 mol/l aqueous phosphoric acidsolution (0.329 mL) at room temperature, and the mixture was stirred atroom temperature for 3 hr. The precipitated solid was collected byfiltration, and crystallized from ethanol/water/diisopropyl ether togive the title compound (97.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90-1.12 (2H, m), 1.52-1.74 (2H, m),1.77-1.94 (2H, m), 1.95-2.21 (3H, m), 2.32-2.39 (1H, m), 2.62 (3H, s),3.34-3.50 (1H, m), 7.56 (1H, s), 7.98-8.04 (1H, m).

Example 1174-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidesuccinate

To a mixture of4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide(100 mg) and ethyl acetate (4 mL) was added a mixture of succinic acid(35.3 mg) and ethanol (1 mL) at 70° C., and the mixture was stirred atroom temperature for 2 hr. The precipitated solid was collected byfiltration, and crystallized from ethanol/water/diisopropyl ether togive the title compound (78.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-1.02 (2H, m), 1.49-1.82 (4H, m),1.82-1.91 (1H, m), 2.03-2.19 (2H, m), 2.20-2.30 (1H, m), 2.40 (4H, s),2.62 (3H, s), 3.31 (2H, dt, J=15.52, 7.76 Hz), 7.51 (1H, d, J=1.14 Hz),7.96 (1H, d, J=1.14 Hz), 10.00 (2H, brs).

Example 1184-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidesulfate A)4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide

To a suspension of4-((1S,2R)-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride (13.3 g), THF (120 mL) and methanol (120 mL) were addedtriethylamine (15.7 mL), triethyl orthoformate (8.32 mL) andcyclobutanone (3.39 mL) at room temperature, and the mixture was stirredat room temperature overnight. Sodium borohydride (2.14 g) was addedunder ice-cooling, and the reaction mixture was stirred at roomtemperature for 1 hr. To the reaction mixture was added saturatedaqueous ammonium chloride solution at 0° C., and the mixture was stirredat 0° C. for 30 min. The organic solvent was evaporated under reducedpressure. To the residue were added saturated aqueous sodium hydrogencarbonate solution and THF, and the mixture was extracted with ethylacetate. The extract was successively washed with water and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (ethyl acetate/methanol) to give thetitle compound (6.35 g).

MS: [M+H]⁺ 335.0.

B)4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidesulfate

To a mixture of 4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-,3,4-thiadiazol-2-yl)thiophene-2-carboxamide (9.51 g) and THF (150 mL)was added 10% aqueous sulfuric acid solution (27.4 mL) at roomtemperature, and the mixture was stirred at room temperature overnight.To the reaction mixture was added ethyl acetate (100 mL), and themixture was further stirred for 1 hr. The precipitated solid wascollected by filtration, and washed with ethyl acetate. The obtainedsolid (10.8 g) was dissolved in ethanol (100 mL) and water (65 mL) at65° C., and the mixture was stirred at 65° C. for 30 min. To thereaction mixture was added dropwise ethyl acetate (250 mL). The reactionmixture was slowly cooled to room temperature, and stirred at roomtemperature overnight. The precipitated solid was collected byfiltration, and washed with ethyl acetate to give the title compound(9.46 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.21-1.32 (1H, m), 1.42 (1H, ddd, J=10.22,6.06, 4.54 Hz), 1.74-1.92 (2H, m), 2.06-2.31 (4H, m), 2.39-2.48 (1H, m),2.63 (3H, s), 2.84 (1H, dt, J=7.48, 4.02 Hz), 3.87 (1H, quin, J=8.05Hz), 7.74 (1H, d, J=1.14 Hz), 8.04 (1H, d, J=1.14 Hz)

Example 1194-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide

To4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride (650 mg) were added ethyl acetate and saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The extract was washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give the title compound (523 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82-1.00 (2H, m), 1.48-1.88 (5H, m),2.01-2.17 (2H, m), 2.18-2.25 (1H, m), 2.62 (3H, s), 3.20-3.41 (3H, m),7.48 (1H, d, J=1.14 Hz), 7.94 (1H, d, J=1.14 Hz).

Example 1205-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide

To5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride (600 mg) were added ethyl acetate and saturated aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overmagnesium sulfate, and concentrated under reduced pressure to give thetitle compound (520 mg).

¹H NMR (300 MHz, CDCl₃) δ 0.06-0.17 (2H, m), 0.42-0.55 (2H, m),0.86-1.04 (2H, m), 1.10-1.22 (1H, m), 1.44-1.57 (2H, m), 1.91-2.13 (3H,m), 2.37-2.50 (1H, m), 2.53-2.66 (2H, m), 3.45-3.61 (2H, m), 3.93-4.05(2H, m), 4.06-4.25 (1H, m), 5.62-5.77 (1H, m), 6.92-6.98 (1H, m), 7.52(1H, d, J=1.5 Hz).

The compounds of Examples 121 and 122 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 1214-((1S,2R)-2-((cyclobutylmethyl)amino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride Example 1224-((1S,2R)-2-((cyclobutylmethyl)amino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamidehydrochloride Example 1234-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidehydrochloride A) methyl4-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate

Methyl 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate (8 g) was fractionated bySFC (column: CHIRALPAK AD, 20 mmID×250 mmL, manufactured by DaicelCorporation, mobile phase: carbon dioxide/methanol=900/100), and theobtained fraction was concentrated under reduced pressure to give methyl4-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate(optical isomer, retention time short) (3.68 g) and methyl4-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate(optical isomer, retention time long) (3.72 g). methyl4-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate(optical isomer, retention time short)

HPLC retention time 4.834 min (column: CHIRALPAK ADH, 4.6 mmID×150 mmL,mobile phase: carbon dioxide/methanol=900/100, flow rate: 2.5 mL/min,temperature: 35° C., detection: UV 220 nm, concentration: 0.5 mg/mL,injection volume: 0.005 mL).

MS: [M-tBu+2H]⁺ 256.1.

methyl4-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate(Optical Isomer, Retention Time Long)

HPLC retention time 6.885 min (column: CHIRALPAK ADH, 4.6 mmID×150 mmL,mobile phase: carbon dioxide/methanol=900/100, flow rate: 2.5 mL/min,temperature: 35° C., detection: UV 220 nm, concentration: 0.5 mg/mL,injection volume: 0.005 mL).

MS: [M-tBu+2H]⁺ 256.1.

B)4-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid

Methyl4-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylate(3.2 g) was dissolved in methanol (20 mL) and tetrahydrofuran (10 mL), 2mol/L aqueous sodium hydroxide solution (12.9 mL) was added at 0° C.,and the mixture was stirred at room temperature overnight. The reactionmixture was acidified with 1 mol/L hydrochloric acid, and extracted withethyl acetate. The extract was washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give the title compound (3.06 g).

MS: [M−H]⁻ 296.0.

C) tert-butyl((1R,2S)-2-(2-methyl-5-((1-methyl-1H-pyrazol-4-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate

4-((1S,2R)-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-5-methylthiophene-2-carboxylicacid (3.06 g), l-methyl-1H-pyrazol-4-amine hydrochloride (1.37 g) andtriethylamine (5.73 mL) were dissolved in DMF (30 mL),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (4.69 g) was added, and the mixture was stirred at40° C. overnight. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate and methanol/ethyl acetate) to givethe title compound (3.7 g).

MS: [M+H]⁺ 377.1

D)4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride

To a suspension of tert-butyl((1R,2S)-2-(2-methyl-5-((1-methyl-1H-pyrazol-4-yl)carbamoyl)thiophen-3-yl)cyclopropyl)carbamate(3.7 g) in ethyl acetate (45 mL) and methanol (25 mL) was added 4 mol/Lhydrogen chloride/ethyl acetate solution (49.1 mL) at 0° C., and themixture was stirred at room temperature overnight. The precipitatedsolid was collected by filtration, and washed with ethyl acetate to givethe title compound (3 g).

MS: [M+H-2HCl]⁺ 277.1.

E)4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide

To a suspension of4-((1S,2R)-2-aminocyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidedihydrochloride (3 g) in methanol (40 mL) were added triethylamine (2.99mL, 21.5 mmol), trimethoxymethane (1.90 mL, 17.2 mmol) and cyclobutanone(0.77 mL, 10.3 mmol) at room temperature. The reaction mixture wasstirred at room temperature overnight, and sodium borohydride (487 mg)was added under cooling at −40° C. The reaction mixture was stirred at−40° C. for 1 hr, saturated aqueous ammonium chloride solution wasadded, and the mixture was concentrated under reduced pressure. To theresidue was added saturated aqueous sodium hydrogen carbonate solution,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (ethyl acetate/methanol) togive the title compound (2 g).

MS: [M+H]⁺ 331.1.

F)4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamidehydrochloride

4N Hydrogen chloride/ethyl acetate solution (6.08 mL, 24.33 mmol) wasadded to a solution of4-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide(2.68 g, 8.11 mmol) in ethyl acetate (20 mL) at 0° C. The precipitatewas collected by filtration, and washed with ethyl acetate to give awhite solid. The obtained white solid was recrystallized from ethanol,water and ethyl acetate to give the title compound (1.920 g) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.10-1.26 (1H, m), 1.51-1.55 (1H, m),1.66-1.94 (2H, m), 2.14-2.36 (4H, m), 2.39-2.50 (4H, m), 2.76-2.81 (1H,m), 3.70-3.93 (4H, m), 7.50-7.57 (2H, m), 7.92 (1H, s), 9.68 (2H, brs),10.33 (1H, s).

The compounds of Examples 124 and 125 could be produced according to theproduction methods described in the present specification, a methodshown in the Examples, or a method analogous thereto.

Example 1244-((1S,2R)-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamidedihydrochloride Example 1255-((1S,2S)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamidehydrochloride

Example compounds are shown in the following Tables. MS in the Tablesshows measured values.

TABLE 1 Ex. No. IUPAC name structure salt MS 1 4-(trans-2-aminocyclopropyl)-5- methyl-N-(5-methyl- 1,3,4-thiadiazol-2-yl)thiophene-2- carboxamide

2HCl 295.0 2 4-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-5-methyl-N-(5-methyl- 1,3,4-thiadiazol-2- yl)thiophene-2- carboxamide

2HCl 349.1 3 5-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(4,4- difluorocyclohexyl)- 1-methyl-1H- pyrazole-3-carboxamide

HCl 353.1 4 5-(trans-2- aminocyclopropyl)-N- (4,4- difluorocyclohexyl)-1-methyl-1H- pyrazole-3- carboxamide

HCl 299.1 5 4-(trans-2- aminocyclopropyl)-N- (5-methyl-1,3,4-thiadiazol-2-yl)-2- naphthamide

2HCl 325.1 6 N-(5-methyl-1,3,4- thiadiazol-2-yl)-4- (trans-2-((tetrahydro-2H- pyran-4- ylmethyl)amino)- cyclopropyl)-2- naphthamide

HCl 421.1 7 4-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(5-methyl-1,3,4- thiadiazol-2-yl)-2- naphthamide

2HCl 379.2 8 N-(4,4- difluorocyclohexyl)- 5-methyl-4-(trans-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-2-carboxamide

HCl 413.2 9 7-(trans-2- aminocyclopropyl)-N- (5-methyl-1,3,4-thiadiazol-2-yl)- 2,3-dihydro-1- benzofuran-5- carboxamide

2HCl 317.0 10 7-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2-yl)- 2,3-dihydro-1-benzofuran-5- carboxamide

2HCl 371.1 11 7-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(4,4- difluorocyclohexyl)- 2,3-dihydro-1- benzofuran-5-carboxamide

HCl 391.2 12 N-(4,4- difluorocyclohexyl)- 7-(trans-2- ((tetrahydro-2H-pyran-4-ylmethyl)- amino)cyclopropyl)- 2,3-dihydro-1- benzofuran-5-carboxamide

HCl 435.2 13 5-(trans-2- aminocyclopropyl)-N- (4,4- difluorocyclohexyl)-6-methylnicotinamide

2HCl 310.2 14 5-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(4,4- difluorocyclohexyl)- 6-methylnicotinamide

2HCl 364.2 15 3-(trans-2- aminocyclopropyl)-N- (5-methyl-1,3,4-thiadiazol-2-yl)-1- naphthamide

2HCl 325.1 16 N-(5-methyl-1,3,4- thiadiazol-2-yl)-3- (trans-2-((tetrahydro-2H- pyran-4- ylmethyl)amino)- cyclopropyl)-1- naphthamide

2HCl 423.2 17 4-(trans-2- (cyclobutylamino)- cyclopropyl)-5-methyl-N-(5-methyl- 1,3,4-thiadiazol-2- yl)thiophene-2- carboxamide

1/2 fuma- rate 349.1 18 4-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(4,4- difluorocyclohexyl)- 5-methylthiophene-2-carboxamide

fuma- rate 369.1 19 4-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-5- methyl-N- (tetrahydro-2H- pyran-4- yl)thiophene-2-carboxamide

fuma- rate 335.1 20 5-methyl-N-(5- methyl-1,3,4- thiadiazol-2-yl)-4-(trans-2- ((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)-thiophene-2- carboxamide

2HCl 391.1 21 N-(4,4-difluoro- cyclohexyl)-5- methyl-4-(trans-2-(tetrahydro-2H- pyran-4-ylamino)- cyclopropyl)thio- phene-2-carboxamide

fuma- rate 399.2 22 4-(trans-2- (cyclobutylamino)- cyclopropyl)-5-methyl-N-(1-methyl- 1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 331.3 23 5-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2- yl)thiophene-3-carboxamide

2HCl 335.1 24 N-(4,4- difluorocyclohexyl)- 5-(trans-2- ((tetrahydro-2H-pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3- carboxamide

HCl 399.2 25 4-(trans-2- aminocyclopropyl)-5- methyl-N-(1-methyl-1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 277.1 26 4-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-5-methyl-N-(5-methyl- 1,3,4-thiadiazol-2- yl)thiophene-2- carboxamide

fuma- rate 349.1 27 4-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2- yl)thiophene-2-carboxamide

2HCl 335.1 28 4-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(4,4- difluorocyclohexyl)- thiophene-2- carboxamide

HCl 355.2 29 N-(4,4- difluorocyclohexyl)- 4-(trans-2- (tetrahydro-2H-pyran-4-ylamino)- cyclopropyl)thio- phene-2-carboxamide

HCl 385.1 30 5-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(4,4- difluorocyclohexyl)- thiophene-3- carboxamide

HCl 355.2 31 N-(4,4-difluoro- cyclohexyl)-5- (trans-2- (tetrahydro-2H-pyran-4-ylamino)- cyclopropyl)thio- phene-3-carboxamide

HCl 385.1 32 5-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-3- carboxamide

HCl 321.1 33 5-(trans-2-(cyclo- butylamino)cyclo- propyl)-N-(5-methyl-1,3,4-thiadiazol-2- yl)thiophene-3- carboxamide

2HCl 335.1 34 5-(trans-2-(cyclo- butylamino)cyclo- propyl)-N-(1-methyl-1H-pyrazol-4- yl)thiophene-3- carboxamide

HCl 317.2 35 4-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(4,4- difluorocyclohexyl)- thiazole-2- carboxamide

HCl 356.2 36 5-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(4,4- difluorocyclohexyl)- thiophene-2- carboxamide

HCl 355.1 37 5-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2- carboxamide

2HCl 335.1 38 N-cyclopentyl-5- ((1R,2R)-2- (tetrahydro-2H-pyran-4-ylamino)- cyclopropyl)thio- phene-3-carboxamide

HCl 335.1 39 N-cyclopentyl-5- ((1S,2S)-2- (tetrahydro-2H-pyran-4-ylamino)- cyclopropyl)thio- phene-3-carboxamide

HCl 335.1 40 N-(5-methyl-1,3,4- thiadiazol-2-yl)-5- ((1R,2R)-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3-carboxamide

2HCl 379.1 41 N-(5-methyl-1,3,4- thiadiazol-2-yl)-5- ((1S,2S)-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3-carboxamide

2HCl 379.1 42 5-((1R,2R)-2- (cyclobutylamino)- cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-3- carboxamide

HCl 321.1 43 5-((1S,2S)-2-(cyclo- butylamino)cyclo- propyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-3- carboxamide

HCl 321.1 44 N-(4,4- difluorocyclohexyl)- 5-((1R,2R)-2- (tetrahydro-2H-pyran-4-ylamino)- cyclopropyl)thio- phene-3-carboxamide

HCl 385.0 45 5-((1R,2R)-2-(cis- (4-aminocyclohexyl)- amino)cyclopropyl)-N-(4,4- difluorocyclohexyl)- thiophene-3- carboxamide or5-((1R,2R)-2-(trans- (4-aminocyclohexyl)- amino)cyclopropyl)- N-(4,4-difluorocyclohexyl)- thiophene-3- carboxamide

2HCl 398.1 46 5-((1R,2R)-2-(cis- (4-aminocyclo- hexyl)amino)cyclo-propyl)-N-(4,4- difluorocyclohexyl)- thiophene-3- carboxamide or5-((1R,2R)-2-(trans- (4-aminocyclohexyl)- amino)cyclopropyl)- N-(4,4-difluorocyclohexyl)- thiophene-3- carboxamide

2HCl 398.1 47 5-((1R,2R)-2-((4,4- difluorocyclohexyl)-amino)cyclopropyl)- N-(tetrahydro-2H- pyran-4- yl)thiophene-3-carboxamide

HCl 385.0 48 5-((1R,2R)-2-((1- cyclopropylpiperi- din-4-yl)amino)-cyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2- yl)thiophene-3-carboxamide

2HCl 403.9 49 N-(5-methyl-1,3,4- thiadiazol-2-yl)-5- ((1R,2R)-2-(tetrahydro-2H- pyran-4-ylamino)- cyclopropyl)thio- phene-3-carboxamide

HCl 364.9 50 N-(2-methyl-1,3- thiazol-5-yl)-5- ((1R,2R)-2-(tetrahydro-2H- pyran-4-ylamino)- cyclopropyl)thio- phene-3-carboxamide

HCl 364.0 51 N-(4,4- difluorocyclohexyl)- 5-((1R,2R)-2- ((tetrahydro-2H-pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3- carboxamide

HCl 399.0 52 5-((1R,2R)-2- ((tetrahydro-2H- pyran-4-ylmethyl)-amino)cyclopropyl)- N-(1-(2,2,2- trifluoroethyl)- piperidin-4-yl)thiophene-3- carboxamide

HCl 446.1 53 N-(2-methyl-1,3- thiazol-5-yl)-5- ((1R,2R)-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3-carboxamide

2HCl 378.0 54 N-(1,3-dimethyl-1H- pyrazol-4-yl)-5- ((1R,2R)-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3-carboxamide

2HCl 375.0 55 N-(1,5-dimethyl-1H- pyrazol-4-yl)-5- ((1R,2R)-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3-carboxamide

2HCl 375.1 56 N-cyclopropyl-5- ((1R,2R)-2- ((tetrahydro-2H-pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3- carboxamide

HCl 321.0 57 4-(trans-2- (cyclobutylamino)- cyclopropyl)-N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2- carboxamide

HCl 335.0 58 N-(5-methyl-1,3,4- thiadiazol-2-yl)-4- (trans-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-2-carboxamide

HCl 379.1 59 4-(trans-2-((1- cyclopropyl- piperidin-4-yl)-amino)cyclopropyl)- N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2-carboxamide

2HCl 404.2 60 3-(4-((((1R,2R)-2- (4-((5-methyl-1,3,4- thiadiazol-2-yl)-carbamoyl)-2- thienyl)cyclopropyl) amino)methyl)- piperidin-1-yl)propanoic acid

3HCl 450.0 61 4-(trans-2- (cyclobutylamino)- cyclopropyl)-N-(1-methyl-1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 317.1 62 4-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(1- methyl-1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 317.0 63 4-(trans-2- (cyclobutylamino)- cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 321.0 64 4-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 321.0 65 5-(trans-2-((cyclo- propylmethyl)amino)-cyclopropyl)-N-(4,4- difluorocyclohexyl)- 2-methylthiophene-3-carboxamide

HCl 369.1 66 N-(4,4- difluorocyclohexyl)- 2-methyl-5-(trans-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3-carboxamide

HCl 413.1 67 N-(4,4-difluoro- cyclohexyl)-2- methyl-5-(trans-2-(tetrahydro-2H- pyran-4-ylamino)- cyclopropyl)thio- phene-3-carboxamide

HCl 399.0 68 5-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-2-methyl-N- (tetrahydro-2H- pyran-4- yl)thiophene-3- carboxamide

HCl 335.1 69 5-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-2-methyl-N-(5-methyl- 1,3,4-thiadiazol-2- yl)thiophene-3- carboxamide

2HCl 349.0 70 2-methyl-N-(5- methyl-1,3,4- thiadiazol-2-yl)-5- (trans-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3-carboxamide

2HCl 393.0 71 5-((1R,2R)-2- ((cyclo- propylmethyl)amino)-cyclopropyl)-N- (tetrahydro-2H- pyran-4- yl)thiophene-3- carboxamide

HCl 321.0 72 N-(5-methyl-1,3,4- thiadiazol-2-yl)-4- ((1S,2R)-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-2-carboxamide

HCl 377.0 73 4-((1R,2S)-2-(cyclo- butylamino)cyclo- propyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 321.0 74 N-(5-methyl-1,3,4- thiadiazol-2-yl)-4- ((1R,2S)-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-2-carboxamide

HCl 379.0 75 4-((1R,2S)-2- ((cyclopropylmethyl) amino)cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 321.0 76 4-((1S,2R)-2- (cyclobutylamino)- cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 321.0 77 4-((1S,2R)-2- ((cyclo- propylmethyl)amino)- cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 321.0 78 4-((1S,2R)-2-((1- cyclopropyl- piperidin-4-yl)-amino)cyclopropyl)- N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2-carboxamide

2HCl 404.0 79 4-((1R,2S)-2-((1- cyclopropyl- piperidin-4-yl)-amino)cyclopropyl)- N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2-carboxamide

2HCl 404.0 80 5-((1R,2R)-2-((1- cyclopropyl- piperidin-4-yl)-amino)cyclopropyl)- N-(4,4- difluorocyclohexyl)- thiophene-3-carboxamide

HCl 424.0 81 N-5-methyl-1,2- oxazol-3-yl)-5- ((1R,2R)-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3-carboxamide

HCl 362.0 82 4-((1S,2R)-2- ((cyclo- propylmethyl)amino)-cyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2- yl)thiophene-2-carboxamide

2HCl 335.0 83 4-((1R,2S)-2- ((cyclo- propylmethyl)amino)-cyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2- yl)thiophene-2-carboxamide

2HCl 335.0 84 4-((1S,2R)-2- (cyclobutylamino)- cyclopropyl)-N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2- carboxamide

2HCl 335.0 85 4-((1R,2S)-2- (cyclobutylamino)- cyclopropyl)-N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2- carboxamide

2HCl 335.0 86 N-(1-ethyl-1H- pyrazol-4-yl)-5- ((1R,2R)-2-((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)- thiophene-3-carboxamide

2HCl 375.1 87 4-((1S,2R)-2- ((cyclo- propylmethyl)amino)-cyclopropyl)-N-(1- methyl-1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 317.1 88 4-((1R,2S)-2- ((cyclo- propylmethyl)amino)-cyclopropyl)-N-(1- methyl-1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 317.1 89 4-((1S,2R)-2-(cyclo- butylamino)cyclo-propyl)-N-(1-methyl- 1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 317.1 90 4-((1R,2S)-2-(cyclo- butylamino)cyclo-propyl)-N-(1-methyl- 1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 317.0 91 5-((1R,2R)-2-((1- acetylpiperidin-4- yl)amino)cyclo-propyl)-N-(4,4- difluorocyclohexyl)- thiophene-3- carboxamide

HCl 426.1 92 5-((1R,2R)-2-((1- (cyclopropyl- carbonyl)piperidin-4-yl)amino)- cyclopropyl)-N-(4,4- difluorocyclohexyl)- thiophene-3-carboxamide

HCl 452.1 93 N-(4,4- difluorocyclohexyl)- 5-methyl-4-((1S,2R)-2-(tetrahydro-2H- pyran-4- ylamino)cyclopropyl) thiophene-2- carboxamide

fuma- rate 399.0 94 N-(4,4- difluorocyclohexyl)- 5-methyl-4-((1R,2S)-2-(tetrahydro-2H- pyran-4- ylamino)cyclopropyl) thiophene-2- carboxamide

fuma- rate 399.0 95 4-((1S,2R)-2- ((cyclopropylmethyl)amino)cyclopropyl)- 5-methyl-N-(5- methyl-1,3,4- thiadiazol-2-yl)thiophene-2- carboxamide

fuma- rate 349.0 96 4-((1R,2S)-2- ((cyclopropylmethyl)amino)cyclopropyl)- 5-methyl-N-(5- methyl-1,3,4- thiadiazol-2-yl)thiophene-2- carboxamide

fuma- rate 349.0 97 5-methyl-N-(5- methyl-1,3,4- thiadiazol-2-yl)-4-((1S,2R)-2- ((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)-thiophene-2- carboxamide

HCl 391.0 98 5-methyl-N-(5- methyl-1,3,4- thiadiazol-2-yl)-4-((1R,2S)-2- ((tetrahydro-2H- pyran-4-ylmethyl)- amino)cyclopropyl)-thiophene-2- carboxamide

HCl 391.0 99 4-((1S,2R)-2- (cyclobutylamino)- cyclopropyl)-5-methyl-N-(5-methyl- 1,3,4-thiadiazol-2- yl)thiophene-2- carboxamide

HCl 349.0 100 4-((1R,2S)-2- (cyclobutylamino)- cyclopropyl)-5-methyl-N-(5-methyl- 1,3,4-thiadiazol-2- yl)thiophene-2- carboxamide

HCl 349.0 101 4-((4-((((1R,2R)-2- (4-((4,4-difluoro- cyclohexyl)-carbamoyl)-2- thienyl)cyclo- propyl)amino)methyl) piperidin-1-yl)methyl)benzoic acid

2HCl 532.1 102 4-((1S,2R)-2- ((cyclopropylmethyl) amino)cyclopropyl)-5-methyl-N-(1- methyl-1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 331.1 103 4-((1R,2S)-2- ((cyclopropylmethyl) amino)cyclopropyl)-5-methyl-N-(1- methyl-1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 331.1 104 4-((1S,2R)-2- (cyclobutylamino)- cyclopropyl)-5-methyl-N-(1-methyl- 1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 331.1 105 4-((1R,2S)-2- (cyclobutylamino)- cyclopropyl)-5-methyl-N-(1-methyl- 1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 331.1 106 4-((1S,2R)-2- ((cyclopropylmethyl) amino)cyclopropyl)-5-methyl-N- (tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 335.0 107 4-((1R,2S)-2- ((cyclopropylmethyl) amino)cyclopropyl)-5-methyl-N- (tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 335.0 108 4-((1S,2R)-2- (cyclobutylamino)- cyclopropyl)-5- methyl-N-(tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 335.0 109 4-((1R,2S)-2- (cyclobutylamino)- cyclopropyl)-5- methyl-N-(tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 335.0 110 4-((((1R,2R)-2-(4- ((4,4-difluoro- cyclohexyl)-carbamoyl)-2- thienyl)cyclopropyl) amino)methyl)benzoic acid

HCl 435.0 111 5-((1R,2R)-2-(((5- amino-1,3,4- oxadiazol-2-yl)-methyl)amino)cyclo- propyl)-N-(4,4- difluorocyclohexyl)- thiophene-3-carboxamide

2HCl 398.0 112 5-((1R,2R)-2- ((cyclobutylmethyl)- amino)cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-3- carboxamide

HCl 335.1 113 5-((1R,2R)-2- ((cyclopropylmethyl) amino)cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-3- carboxamide

L-mal- ate 321.2 114 5-((1R,2R)-2- ((cyclopropylmethyl)amino)cyclopropyl)- N-(tetrahydro-2H- pyran-4- yl)thiophene-3-carboxamide

succi- nate 321.2 115 5-((1R,2R)-2- ((cyclopropylmethyl)amino)cyclopropyl)- N-(tetrahydro-2H- pyran-4- yl)thiophene-3-carboxamide

fuma- rate 321.1 116 4-((1S,2R)-2- (cyclobutylamino)- cyclopropyl)-N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2- carboxamide

H₃PO₄ 335.1 117 4-((1S,2R)-2- (cyclobutylamino)- cyclopropyl)-N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2- carboxamide

succi- nate 335.1 118 4-((1S,2R)-2- (cyclobutylamino)-cyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2- yl)thiophene-2-carboxamide

H₂SO₄ 335.1 119 4-((1S,2R)-2- (cyclobutylamino)- cyclopropyl)-N-(5-methyl-1,3,4- thiadiazol-2- yl)thiophene-2- carboxamide

335.0 120 5-((1R,2R)-2- ((cyclopropylmethyl) amino)cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-3- carboxamide

321.1 121 4-((1S,2R)-2- ((cyclobutylmethyl)- amino)cyclopropyl)-5-methyl-N-(1- methyl-1H-pyrazol-4- yl)thiophene-2- carboxamide

2HCl 345.1 122 4-((1S,2R)-2- ((cyclobutylmethyl)- amino)cyclopropyl)-5-methyl-N- (tetrahydro-2H- pyran-4- yl)thiophene-2- carboxamide

HCl 349.1 123 4-((1S,2R)-2- (cyclobutylamino)- cyclopropyl)-5-methyl-N-(1-methyl- 1H-pyrazol-4- yl)thiophene-2- carboxamide

HCl 331.2 124 4-((1S,2R)-2- aminocyclopropyl)-N- (5-methyl-1,3,4-thiadiazol-2- yl)thiophene-2- carboxamide

2HCl 281.1 125 5-((1S,2S)-2- ((cyclopropylmethyl) amino)cyclopropyl)-N-(tetrahydro-2H- pyran-4- yl)thiophene-3- carboxamide

HCl 321.2

Other preferable specific examples of the compound represented by theformula (I) include the following compounds shown in the Examples, anoptically active form thereof, and a mixture of optically active formsthereof. The following compounds shown in the Examples, an opticallyactive form thereof, and a mixture of optically active forms thereof canbe produced according to the aforementioned production methods, a methodshown in the Examples, or a method analogous thereto. The relativeconfiguration of the substituent on the cyclopropane ring is cis ortrans, preferably trans.

Example A14-(2-(cyclobutylamino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample A24-(2-(cyclobutylamino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample A34-(2-(cyclobutylamino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-2-carboxamideExample A44-(2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamideExample A54-(2-(cyclobutylamino)cyclopropyl)-N-cyclopentylthiophene-2-carboxamideExample A64-(2-(cyclobutylamino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamideExample A74-(2-(cyclobutylamino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-2-carboxamideExample A84-(2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample A94-(2-(cyclobutylamino)cyclopropyl)-N-(3-methyl-1,2-oxazol-5-yl)thiophene-2-carboxamideExample A104-(2-(cyclobutylamino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)thiophene-2-carboxamideExample A11 4-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide ExampleA124-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample A134-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample A144-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-2-carboxamideExample A15N-cyclopentyl-4-(2-((cyclopropylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A164-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-2-carboxamideExample A174-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample A184-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-methyl-1,2-oxazol-5-yl)thiophene-2-carboxamideExample A194-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)thiophene-2-carboxamideExample A204-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(oxetan-3-yl)thiophene-2-carboxamideExample A214-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)thiophene-2-carboxamideExample A224-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)thiophene-2-carboxamideExample A234-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-2-thienyl)thiophene-2-carboxamideExample A244-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(pyridin-4-yl)thiophene-2-carboxamideExample A254-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-methyl-1,3-oxazol-5-yl)thiophene-2-carboxamideExample A264-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamideExample A274-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-methyloxetan-3-yl)thiophene-2-carboxamideExample A28N-cyclopropyl-4-(2-((cyclopropylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A29N-cyclopentyl-4-(2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-2-carboxamideExample A30N-(2-methyl-1,3-thiazol-5-yl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-2-carboxamideExample A314-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamideExample A324-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample A334-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-2-carboxamideExample A34N-cyclopentyl-4-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A354-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamideExample A364-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-2-carboxamideExample A374-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample A384-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(3-methyl-1,2-oxazol-5-yl)thiophene-2-carboxamideExample A394-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)thiophene-2-carboxamideExample A40N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A41N-(1-ethyl-1H-pyrazol-4-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A42N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A43N-cyclopentyl-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A444-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-2-carboxamideExample A45N-(5-methyl-1,2-oxazol-3-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A46N-(3-methyl-1,2-oxazol-5-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A47N-(2-methyl-1,3-thiazol-5-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A48N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A49N-(1-methyl-1H-pyrazol-4-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A50N-(1-ethyl-1H-pyrazol-4-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A51N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A52N-cyclopentyl-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A53N-(4,4-difluorocyclohexyl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A54N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A55N-(5-methyl-1,2-oxazol-3-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A56N-(3-methyl-1,2-oxazol-5-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A57N-(2-methyl-1,3-thiazol-5-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample A584-(2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamideExample A594-(2-(cyclobutylamino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample A60N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A61N-(4,4-difluorocyclohexyl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample A624-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamideExample B14-(2-(cyclobutylamino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylthiophene-2-carboxamideExample B24-(2-(cyclobutylamino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)-5-methylthiophene-2-carboxamideExample B34-(2-(cyclobutylamino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-methylthiophene-2-carboxamideExample B44-(2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamideExample B54-(2-(cyclobutylamino)cyclopropyl)-N-cyclopentyl-5-methylthiophene-2-carboxamideExample B64-(2-(cyclobutylamino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamideExample B74-(2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-2-carboxamideExample B84-(2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample B94-(2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(3-methyl-1,2-oxazol-5-yl)thiophene-2-carboxamideExample B104-(2-(cyclobutylamino)cyclopropyl)-5-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-2-carboxamideExample B114-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample B124-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylthiophene-2-carboxamideExample B134-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)-5-methylthiophene-2-carboxamideExample B144-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-methylthiophene-2-carboxamideExample B15 N-cyclopentyl-4-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methylthiophene-2-carboxamide Example B164-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-2-carboxamideExample B174-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample B184-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(3-methyl-1,2-oxazol-5-yl)thiophene-2-carboxamideExample B194-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-2-carboxamideExample B204-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(oxetan-3-yl)thiophene-2-carboxamideExample B214-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)-5-methylthiophene-2-carboxamideExample B224-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)thiophene-2-carboxamideExample B234-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-2-thienyl)thiophene-2-carboxamideExample B244-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(pyridin-4-yl)thiophene-2-carboxamideExample B254-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(2-methyl-1,3-oxazol-5-yl)thiophene-2-carboxamideExample B264-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamideExample B274-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methyl-N-(3-methyloxetan-3-yl)thiophene-2-carboxamideExample B28N-cyclopropyl-4-(2-((cyclopropylmethyl)amino)cyclopropyl)-5-methylthiophene-2-carboxamideExample B29N-cyclopentyl-5-methyl-4-(2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-2-carboxamideExample B305-methyl-N-(2-methyl-1,3-thiazol-5-yl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-2-carboxamideExample B314-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamideExample B32 4-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)-5-methylthiophene-2-carboxamideExample B334-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-methylthiophene-2-carboxamideExample B34N-cyclopentyl-4-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-5-methylthiophene-2-carboxamideExample B354-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamideExample B364-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-5-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-2-carboxamideExample B374-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample B384-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-5-methyl-N-(3-methyl-1,2-oxazol-5-yl)thiophene-2-carboxamideExample B394-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-5-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-2-carboxamideExample B40N-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methyl-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample B41N-(1-ethyl-1H-pyrazol-4-yl)-5-methyl-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample B42N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-methyl-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample B43N-cyclopentyl-5-methyl-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample B445-methyl-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-2-carboxamideExample B455-methyl-N-(5-methyl-1,2-oxazol-3-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample B465-methyl-N-(3-methyl-1,2-oxazol-5-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample B475-methyl-N-(2-methyl-1,3-thiazol-5-yl)-4-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-2-carboxamideExample B485-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample B495-methyl-N-(1-methyl-1H-pyrazol-4-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample B50N-(1-ethyl-1H-pyrazol-4-yl)-5-methyl-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample B51N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-methyl-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample B52N-cyclopentyl-5-methyl-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample B53N-(4,4-difluorocyclohexyl)-5-methyl-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample B545-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample B555-methyl-N-(5-methyl-1,2-oxazol-3-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample B565-methyl-N-(3-methyl-1,2-oxazol-5-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample B575-methyl-N-(2-methyl-1,3-thiazol-5-yl)-4-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-2-carboxamideExample C15-(2-(cyclobutylamino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample C25-(2-(cyclobutylamino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample C35-(2-(cyclobutylamino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-3-carboxamideExample C45-(2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamideExample C55-(2-(cyclobutylamino)cyclopropyl)-N-cyclopentylthiophene-3-carboxamideExample C65-(2-(cyclobutylamino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamideExample C75-(2-(cyclobutylamino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-3-carboxamideExample C85-(2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample C95-(2-(cyclobutylamino)cyclopropyl)-N-(3-methyl-1,2-oxazol-5-yl)thiophene-3-carboxamideExample C105-(2-(cyclobutylamino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample C115-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample C125-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample C135-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample C145-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-3-carboxamideExample C15N-cyclopentyl-5-(2-((cyclopropylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample C165-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-3-carboxamideExample C175-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample C185-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-methyl-1,2-oxazol-5-yl)thiophene-3-carboxamideExample C195-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample C205-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(oxetan-3-yl)thiophene-3-carboxamideExample C21 5-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)thiophene-3-carboxamide ExampleC225-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)thiophene-3-carboxamideExample C235-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-2-thienyl)thiophene-3-carboxamideExample C245-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(pyridin-4-yl)thiophene-3-carboxamideExample C255-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-methyl-1,3-oxazol-5-yl)thiophene-3-carboxamideExample C26 5-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample C275-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-methyloxetan-3-yl)thiophene-3-carboxamideExample C28N-cyclopropyl-5-(2-((cyclopropylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample C29N-cyclopentyl-5-(2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamideExample C30N-(2-methyl-1,3-thiazol-5-yl)-5-(2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamideExample C315-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample C325-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample C335-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-3-carboxamideExample C34N-cyclopentyl-5-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C355-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamideExample C365-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-3-carboxamideExample C375-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample C385-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(3-methyl-1,2-oxazol-5-yl)thiophene-3-carboxamideExample C395-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample C40N-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample C41N-(1-ethyl-1H-pyrazol-4-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample C42N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample C43N-cyclopentyl-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample C445-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-3-carboxamideExample C45N-(5-methyl-1,2-oxazol-3-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample C46N-(3-methyl-1,2-oxazol-5-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample C47N-(2-methyl-1,3-thiazol-5-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample C48N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C49N-(1-methyl-1H-pyrazol-4-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C50N-(1-ethyl-1H-pyrazol-4-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C51N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C52N-cyclopentyl-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C53N-(4,4-difluorocyclohexyl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C54N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C55N-(5-methyl-1,2-oxazol-3-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C56N-(3-methyl-1,2-oxazol-5-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample C57N-(2-methyl-1,3-thiazol-5-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D15-(2-(cyclobutylamino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methylthiophene-3-carboxamideExample D25-(2-(cyclobutylamino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)-2-methylthiophene-3-carboxamideExample D35-(2-(cyclobutylamino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methylthiophene-3-carboxamideExample D45-(2-(cyclobutylamino)cyclopropyl)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamideExample D55-(2-(cyclobutylamino)cyclopropyl)-N-cyclopentyl-2-methylthiophene-3-carboxamideExample D65-(2-(cyclobutylamino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-2-methylthiophene-3-carboxamideExample D75-(2-(cyclobutylamino)cyclopropyl)-2-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-3-carboxamideExample D85-(2-(cyclobutylamino)cyclopropyl)-2-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample D95-(2-(cyclobutylamino)cyclopropyl)-2-methyl-N-(3-methyl-1,2-oxazol-5-yl)thiophene-3-carboxamideExample D105-(2-(cyclobutylamino)cyclopropyl)-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample D115-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample D125-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methylthiophene-3-carboxamideExample D135-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)-2-methylthiophene-3-carboxamideExample D145-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methylthiophene-3-carboxamideExample D15N-cyclopentyl-5-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methylthiophene-3-carboxamideExample D165-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-3-carboxamideExample D175-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample D185-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(3-methyl-1,2-oxazol-5-yl)thiophene-3-carboxamideExample D195-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample D205-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(oxetan-3-yl)thiophene-3-carboxamideExample D215-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)-2-methylthiophene-3-carboxamideExample D225-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)thiophene-3-carboxamideExample D235-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(5-methyl-2-thienyl)thiophene-3-carboxamideExample D245-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(pyridin-4-yl)thiophene-3-carboxamideExample D255-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(2-methyl-1,3-oxazol-5-yl)thiophene-3-carboxamideExample D265-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample D275-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(3-methyloxetan-3-yl)thiophene-3-carboxamideExample D28N-cyclopropyl-5-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methylthiophene-3-carboxamideExample D29N-cyclopentyl-2-methyl-5-(2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamideExample D302-methyl-N-(2-methyl-1,3-thiazol-5-yl)-5-(2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamideExample D315-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample D325-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)-2-methylthiophene-3-carboxamideExample D335-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methylthiophene-3-carboxamideExample D34N-cyclopentyl-5-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-2-methylthiophene-3-carboxamideExample D355-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-2-methylthiophene-3-carboxamideExample D365-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-2-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-3-carboxamideExample D375-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample D385-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-2-methyl-N-(3-methyl-1,2-oxazol-5-yl)thiophene-3-carboxamideExample D395-(2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample D40N-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methyl-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample D41N-(1-ethyl-1H-pyrazol-4-yl)-2-methyl-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample D42N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample D43N-cyclopentyl-2-methyl-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample D442-methyl-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)thiophene-3-carboxamideExample D452-methyl-N-(5-methyl-1,2-oxazol-3-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample D462-methyl-N-(3-methyl-1,2-oxazol-5-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample D472-methyl-N-(2-methyl-1,3-thiazol-5-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample D482-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D492-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D50N-(1-ethyl-1H-pyrazol-4-yl)-2-methyl-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D51N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D52N-cyclopentyl-2-methyl-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D53N-(4,4-difluorocyclohexyl)-2-methyl-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D542-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D552-methyl-N-(5-methyl-1,2-oxazol-3-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D562-methyl-N-(3-methyl-1,2-oxazol-5-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D572-methyl-N-(2-methyl-1,3-thiazol-5-yl)-5-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)thiophene-3-carboxamideExample D585-(2-(cyclobutylamino)cyclopropyl)-2-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample D595-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample D602-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample D615-(2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-2-methylthiophene-3-carboxamideExample D62N-(4,4-difluorocyclohexyl)-2-methyl-5-(2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)thiophene-3-carboxamideExample D63N-(4,4-difluorocyclohexyl)-2-methyl-5-(2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)thiophene-3-carboxamideExample D645-(2-((cyclopropylmethyl)amino)cyclopropyl)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamideExample E14-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamideExample E24-(2-((3-aminocyclobutyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamideExample E3 5-(2-((3-aminocyclobutyl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample E45-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample E54-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamideExample E64-(2-((4-aminocyclohexyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamideExample E75-(2-((4-aminocyclohexyl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample E85-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)thiophene-3-carboxamideExample E94-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(-ethyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample E10 4-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)-5-methylthiophene-2-carboxamideExample E115-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1-ethyl-H-pyrazol-4-yl)-2-methylthiophene-3-carboxamideExample E125-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample E13 4-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiophene-2-carboxamide ExampleE144-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)-5-methylthiophene-2-carboxamideExample E155-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)-2-methylthiophene-3-carboxamideExample E165-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample E174-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1-methyl-TH-pyrazol-4-yl)thiophene-2-carboxamideExample E184-(2-((3-aminocyclobutyl)amino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample E195-(2-((3-aminocyclobutyl)amino)cyclopropyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample E205-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1-methyl-TH-pyrazol-4-yl)thiophene-3-carboxamideExample E214-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample E224-(2-((4-aminocyclohexyl)amino)cyclopropyl)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample E235-(2-((4-aminocyclohexyl)amino)cyclopropyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample E245-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample E254-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample E264-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylthiophene-2-carboxamideExample E275-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methylthiophene-3-carboxamideExample E285-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample E294-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)thiophene-2-carboxamideExample E304-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylthiophene-2-carboxamideExample E315-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methylthiophene-3-carboxamideExample E325-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)thiophene-3-carboxamideExample E334-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-2-carboxamideExample E344-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-methylthiophene-2-carboxamideExample E355-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methylthiophene-3-carboxamideExample E365-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-3-carboxamideExample E374-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-2-carboxamideExample E384-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5-methylthiophene-2-carboxamideExample E39 5-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methylthiophene-3-carboxamideExample E405-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)thiophene-3-carboxamideExample E414-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamideExample E424-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamideExample E43 5-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-2-methylthiophene-3-carboxamideExample E44 5-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamide ExampleE454-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-2-carboxamideExample E464-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-5-methylthiophene-2-carboxamideExample E475-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)-2-methylthiophene-3-carboxamideExample E485-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)thiophene-3-carboxamideExample E494-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample E504-(2-((3-aminocyclobutyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample E515-(2-((3-aminocyclobutyl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample E525-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample E534-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample E544-(2-((4-aminocyclohexyl)amino)cyclopropyl)-5-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-2-carboxamideExample E555-(2-((4-aminocyclohexyl)amino)cyclopropyl)-2-methyl-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample E565-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)thiophene-3-carboxamideExample E57 4-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(2-methyl-,3-thiazol-5-yl)thiophene-2-carboxamide Example E584-(2-((3-aminocyclobutyl)amino)cyclopropyl)-5-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-2-carboxamideExample E595-(2-((3-aminocyclobutyl)amino)cyclopropyl)-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample E60 5-(2-((3-aminocyclobutyl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample E614-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)thiophene-2-carboxamideExample E624-(2-((4-aminocyclohexyl)amino)cyclopropyl)-5-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-2-carboxamideExample E635-(2-((4-aminocyclohexyl)amino)cyclopropyl)-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample E645-(2-((4-aminocyclohexyl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)thiophene-3-carboxamideExample E654-(2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamideExample E664-(2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamideExample E675-(2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamideExample E68 5-(2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide ExampleE694-(2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamideExample E704-(2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamideExample E715-(2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamideExample E725-(2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamideExperimental Example 1

The genetic engineering method described below was performed accordingto the method described in a book (Maniatis et al., Molecular Cloning,Cold Spring Harbor Laboratory, 1989) or the method described in theprotocol attached to the reagent.

(1) Construction of GST-Tagged Expression Vector Having TEV ProteaseCleavage Sequence

A GST-tagged expression vector having TEV Protease cleavage sequence wasconstructed by successive 2 times of PCR method. Firstly, PCR wasperformed using pGEX6P1 (GE Healthcare) as a template, two primers

GST-Sw-F: [SEQ ID NO: 1] 5′-AGAATCATTTAAATGGTGATCATGTAACCCATCCT-3′GST-Tv-R1: [SEQ ID NO: 2]5′-CGCCCTGAAAGTACAGGTTCTCATCCGATTTTGGAGGATGGTCG-3′and PrimeStar GXL DNA Polymerase (Takara Bio Inc.). Template DNA 0.5 μL,PrimeStar GXL DNA Polymerase Buffer 10 μL, 2.5 mM dNTP solution 4 μL, 10μM primer solution each 1.5 μL, PrimeStar GXL DNA Polymerase 1 μL, andsterilized distilled water 31.5 μL were mixed. After a treatment at 98°C. for 1 min, the PCR was started with 35 repeats of reactions at 98° C.for 10 seconds, at 65° C. for 5 seconds, and at 72° C. for 25 seconds,followed by a reaction at 72° C. for 1 min. Then, PCR was performedusing the obtained PCR product as a template, two primers

GST-Sw-F: [SEQ ID NO: 1] 5′-AGAATCATTTAAATGGTGATCATGTAACCCATCCT-3′GST-Tv-R2: [SEQ ID NO: 3] 5′-ATAATAGGATCCGCCCTGAA2GTACAGGTTCTC-3′and PrimeStar GXL DNA Polymerase. Template DNA 0.5 μL, PrimeStar GXL DNAPolymerase Buffer 10 μL, 2.5 mM dNTP solution 4 μL, 10 μM primersolution each 1.5 μL, PrimeStar GXL DNA Polymerase 1 μL, and sterilizeddistilled water 31.5 μL were mixed. After a treatment at 98° C. for 1min, the PCR was started with 25 repeats of reactions at 98° C. for 10seconds, at 65° C. for 5 seconds, and at 72° C. for 25 seconds, followedby a reaction at 72° C. for 1 min. The obtained PCR product waselectrophoresed on agarose gel (1%), and an about 0.3 kbp DNA fragmentcontaining a part of the GST gene was recovered from the gel. Therecovered DNA fragment was cleaved with restriction enzymes Swa I (NewEngland Biolabs) and Bam HI (Takara Bio Inc.), and inserted into the SwaI/Bam HI site of pGEX6P1 to construct an expression vector pGEX7V1.(2) Cloning of Human LSD1 (AOF2) cDNA

Human LSD1 cDNA was cloned by PCR method using brain cDNA Library(Takara Bio Inc.) as a template, two primers

hLSD1-NheI-ko-F: [SEQ ID NO: 4]5′-TATTATGCTAGCGCCACCATGTTATCTGGGAAGAAGGCGGCAGC--3′ hLSD1-St-NotI-R:[SEQ ID NO: 5] 5′-TATTATGCGGCCGCTCACATGCTTGGGGACTGCTGTGC-3′and Pyrobest DNA Polymerase (Takara Bio Inc.). Template DNA 0.5 μL,Pyrobest DNA Polymerase Buffer 5 μL, 2.5 mM dNTP solution 4 μL, 10 μMprimer solution each 2.5 μL, Pyrobest DNA Polymerase 0.5 μL, andsterilized distilled water 35 μL were mixed. After a reaction at 98° C.for 1 min, the PCR was started with 35 repeats of reactions at 98° C.for 10 seconds, at 68° C. for 5 seconds, and at 72° C. for 2.5 min,followed by a reaction at 72° C. for 1 min. The obtained PCR product waselectrophoresed on agarose gel (1%), and an about 2.5 kbp DNA fragmentcontaining the human LSD1 cDNA was recovered from the gel. The recoveredDNA fragment was cleaved with restriction enzymes Nhe I and Not I(Takara Bio Inc.), and inserted into the Nhe I/Not I site of pcDNA3.1(+)(Invitrogen) to construct an expression plasmid pcDNA3.1/hLSD1.(3) Construction of Expression Plasmid for Human LSD1(172-833) inEscherichia coli

A plasmid for expression of human LSD1(172-833) in Escherichia coli wasconstructed by PCR method using pcDNA3.1/hLSD1 as a template, twoprimers

hLSD1-172aa-Bgl2-F: [SEQ ID NO: 6]5′-ATAATAAGATCTTCGGGTGTGGAGGGCGCAGCTT-3′ hLSD1-833aa-St-NotI-R:[SEQ ID NO: 7] 5′-ATAATAGOGGCCGCCATGGCCCCCAAAAACTGGTCTGCA-3′and PrimeStar MAX DNA Polymerase (Takara Bio Inc.). Template DNA 1 μL,PrimeStar MAX DNA Polymerase Enzyme PreMix 25 μL, 10 μM primer solutioneach 1.5 μL, and sterilized distilled water 21 μL were mixed. After areaction at 98° C. for 1 min, the PCR was started with 25 repeats ofreactions at 98° C. for 10 seconds and at 68° C. for 8 seconds, followedby a reaction at 72° C. for 1 min. The obtained PCR product waselectrophoresed on agarose gel (1%), and an about 2 kbp DNA fragmentcontaining human LSD1(172-833) cDNA was recovered from the gel. Therecovered DNA fragment was cleaved with restriction enzymes Bgl II andNot I (Takara Bio Inc.), and inserted into the Bam HI/Not I site ofpGEX7V1 to construct an expression plasmid pGEX7V1/GST-hLSD1(172-833).(4) Preparation of LSD1

Escherichia coli C43(DE3) pLysS was transformed with the expressionplasmid pGEX7V1/GST-hLSD1(172-833). The obtained recombinant Escherichiacoli was inoculated in a TB medium (1.2% tryptone, 2.4% yeast extract,0.4% glycerol, 17 mM potassium dihydrogen phosphate and 72 mMdipotassium hydrogen phosphate) added with 100 mg/L ampicillin and 35mg/L chloramphenicol, and cultured at 37° C. When the turbidity reached500 Klett units, the culture temperature was changed to 16° C., IPTG(Isopropyl β-D-1-thiogalactopyranoside) having a final concentration of0.5 mM was added to induce expression, and the cells were culturedfurther for 14 hr. The culture medium was centrifuged at 6,000 g for 15min, and Escherichia coli pellets were recovered.

Escherichia coli pellets for 12 L of the culture medium were suspendedin 1000 mL of PBS (Immuno-Biological Laboratories Co., Ltd.), 0.15 MNaCl, 5% (V/V) Glycerol (Buffer A), and 5000 units Benzonase (Merck),1000 mg Lysozyme, and 10 tablets of Protease Inhibitor (Roche) wereadded. Using Branson ultrasonic disintegrator, the suspension wasdisrupted by ultrasonication for 3 min, and centrifuged at 33,000 g for60 min, and the supernatant was recovered. The supernatant was appliedto two GSTrap 4B 5 mL columns (GE Healthcare) equilibrated in advancewith 0.1 M Tris (pH 8.0), 0.15 M NaCl, 5% (V/V) Glycerol (Buffer B), andthe columns were each washed with 30 mL of Buffer B. GST-hLSD1(172-833)was eluted from each column with Buffer B added with 13 mL of GSH withthe final concentration 20 mM, applied to two HiLoad 26/60 Superdex 200pg columns (GE Healthcare) equilibrated in advance with Buffer B, andeluted with 380 mL of Buffer B. Total 60 mL ofGST-hLSD1(172-833)-containing fraction was diluted 5-fold with 20 mMTris (pH 8.0) (Buffer C), applied to Mono Q 10/100 GL column (GEHealthcare) equilibrated in advance with Buffer C, and 0-500 mM NaClgradient elution was performed to give purified GST-hLSD1(172-833). 3.4mg of His-TEV protease was added to about 34 mg of GST-hLSD1(172-833),and the mixture was treated with 50 mM Tris (pH 8.0), 0.5 mM EDTA, 1 mMDTT at 4° C. for 16 hr to cleave the GST tag. The reaction mixture afterthe cleavage reaction was applied to two series-coupled columns withNi-NTA Superflow Cartridges 1 mL (QIAGEN), and GSTrap 4B 5 mL column (GEHealthcare) equilibrated in advance with Buffer A added with Imidazoleat a final concentration of 20 mM, and a flow-through fractioncontaining hLSD1(172-833) free of GST-tag was recovered. It wasconcentrated to 10 mL with AmiconUltra 15 (NWCO 30K) (Millipore Japan),and purified with HiLoad 26/60 Superdex 200 pg column (GE Healthcare)equilibrated with Buffer A to give hLSD1 purified product (8.4 mg). Theprotein concentration of hLSD1 was measured by BCA Protein Assay Kit(Thermo Fisher Scientific K.K.) using bovine serum albumin as thestandard.

(5) Measurement of LSD1 Inhibitory Activity

A test compound dissolved in DMSO was added by to a reaction solution(50 mM Tris-HCl (pH 8.0), 0.1% BSA, 1 mM DTT) containing LSD1 enzyme,and the mixture was reacted at room temperature for 60 min.Biotin-histone H3 mono methylated K4 peptide solution(NH2-ART(me-K)QTARKSTGGKAPRKQLAGGK(Biotin)-CONH2) was added to start thereaction. After reaction at room temperature for 5 min, 2-PCPA solutionwas added to terminate the reaction. A detection solution (800 mMpotassium fluoride, 0.1% BSA) containing europium-labeled anti-histoneH3 antibody (Wako Pure Chemical Industries, Ltd.) and Streptavidin-XL665(Cisbio) was further added, and the mixture was left standing for 60min. A time-resolved fluorescence (excitation 320 nm, emission 615 nm,665 nm) was measured by Envision (PerkinElmer). The LSD1 inhibitory rate(%) of the test compound was calculated by the following formula.inhibitory rate (%)=(1−(test compound count−blank)÷(control−blank))×100

The count of the LSD1 enzyme reaction mixture under compoundnon-addition conditions is indicated as control, and the count undercompound non-addition and LSD1 enzyme non-addition conditions isindicated as blank. A concentration necessary for achieving 50%inhibitory rate was taken as IC₅₀ value. The results are shown in Table2.

Experimental Example 2

(1) Measurement of MAO-A Inhibitory Activity

The MAO-A inhibitory activity evaluation described below followed theprotocol of MAO-Glo (registered trademark) Assay of Promega KK.

A test compound dissolved in DMSO was added to a reaction solution (100mM HEPES (pH 7.5), 5% glycerol) containing MAO-A enzyme (Sigma-AldrichCo. LLC.), and the mixture was reacted at room temperature for 15 min.MAO substrate (Promega KK) was added to start the reaction. Afterreaction at room temperature for 60 min, Luciferine detection reagent(Promega KK) was added to terminate the reaction. After reaction at roomtemperature for 20 min with stirring, the luminescence was measured byEnvision (PerkinElmer). The MAO-A inhibitory rate (%) of the testcompound was calculated by the following formula.inhibitory rate (%)=(1−(test compound count−blank)÷(control−blank))×100

The count of the MAO-A enzyme reaction mixture under compoundnon-addition conditions is indicated as control, and the count undercompound non-addition and MAO-A enzyme non-addition conditions isindicated as blank. A concentration necessary for achieving 50%inhibitory rate was taken as IC₅₀ value. The results are shown in Table2.

(2) Measurement of MAO-B Inhibitory Activity

The MAO-B inhibitory activity evaluation described below followed theprotocol of MAO-Glo (registered trademark) Assay of Promega KK.

A test compound dissolved in DMSO was added to a reaction solution (100mM HEPES (pH 7.5), 5% glycerol, 10% DMSO) containing MAO-B enzyme(Sigma-Aldrich Co. LLC.), and the mixture was reacted at roomtemperature for 15 min. MAO substrate (Promega KK) was added to startthe reaction. After reaction at room temperature for 60 min, Luciferinedetection reagent (Promega KK) (50 μL) was added to terminate thereaction. After reaction at room temperature for 20 min with stirring,the luminescence was measured by Envision (PerkinElmer). The MAO-Binhibitory rate (%) of the test compound was calculated by the followingformula.inhibitory rate (%)=(1−(test compound count−blank)÷(control−blank))×100

The count of the MAO-B enzyme reaction mixture under compoundnon-addition conditions is indicated as control, and the count undercompound non-addition and MAO-B enzyme non-addition conditions isindicated as blank. A concentration necessary for achieving 50%inhibitory rate was taken as IC₅₀ value. The results are shown in Table2.

TABLE 2 LSD1 MAO-A MAO-B Example No. IC₅₀ value (μM) IC₅₀ value (μM)IC₅₀ value (μM) 1 1.3 >100 >100 2 0.33 >100 >100 3 0.29 >100 >100 41.7 >100 >100 5 4.6 >100 >100 6 0.11 >100 >100 7 0.26 82 >100 80.25 >100 >100 9 3.0 >100 >100 10 0.23 >100 >100 11 0.18 >100 >100 12<0.1 >100 >100 13 12 >100 93 14 2.4 >100 28 15 0.73 89 66 16<0.1 >100 >100 17 0.22 >100 >100 18 0.26 >100 >100 19 0.65 >100 >100 20<0.1 >100 >100 21 0.23 >100 88 22 0.14 >100 >100 23 <0.1 >100 >100 24<0.1 >100 >100 25 3.0 >100 >100 26 0.50 >100 >100 27 0.33 >100 >100 28<0.1 >100 >100 29 0.40 >100 >100 30 <0.1 >100 >100 31 <0.1 >100 >100 32<0.1 >100 >100 33 <0.1 >100 >100 34 <0.1 >100 >100 35 0.68 >100 >100 363.8 22 6.0 37 99 85 90 38 <0.1 >100 >100 39 <0.1 23 >100 40<0.1 >100 >100 41 <0.1 67 >100 42 <0.1 >100 >100 43 0.13 >100 >100 44<0.1 >100 100 45 <0.1 >100 >100 46 <0.1 >100 >100 47 <0.1 >100 >100 48<0.1 31 >100 49 <0.1 >100 >100 50 <0.1 >100 >100 51 <0.1 >100 >100 52<0.1 >100 >100 53 <0.1 61 96 54 <0.1 >100 >100 55 <0.1 >100 >100 56<0.1 >100 >100 57 0.44 >100 >100 58 <0.1 >100 >100 59 <0.1 >100 >100 60<0.1 >100 >100 61 <0.1 >100 >100 62 <0.1 >100 >100 63 0.32 >100 >100 640.30 >100 >100 65 <0.1 25 >100 66 <0.1 98 >100 67 0.10 76 >100 680.14 >100 >100 69 <0.1 33 >100 70 <0.1 10 23 71 <0.1 >100 >100 72<0.1 >100 >100 73 0.58 >100 >100 74 <0.1 >100 >100 75 0.34 >100 >100 760.20 >100 >100 77 0.36 >100 >100 78 <0.1 >100 >100 79 0.27 >100 >100 80<0.1 >100 >100 81 <0.1 36 >100 82 0.24 >100 >100 83 0.28 >100 >100 840.23 >100 >100 85 0.81 >100 >100 86 <0.1 87 >100 87 0.18 >100 >100 88<0.1 >100 >100 89 <0.1 >100 >100 90 0.10 >100 >100 91 <0.1 >100 >100 92<0.1 >100 >100 93 0.16 >100 >100 94 0.21 >100 >100 95 0.18 >100 >100 960.59 >100 >100 97 <0.1 >100 >100 98 0.27 >100 >100 99 <0.1 >100 >100 1000.82 >100 >100 101 <0.1 >100 >100 102 0.21 >100 >100 103 0.15 >100 >100104 <0.1 >100 >100 105 0.21 >100 >100 106 0.44 >100 >100 1071.40 >100 >100 108 0.34 >100 >100 109 2.30 >100 >100 110 <0.1 49 >100111 0.10 61 >100 112 <0.1 >100 >100 113 <0.1 >100 >100 114<0.1 >100 >100 115 <0.1 >100 >100 116 0.29 >100 >100 117 0.26 >100 >100118 0.24 >100 >100 119 0.19 >100 >100 120 <0.1 >100 >100 1210.12 >100 >100 122 0.17 >100 >100 123 0.10 >100 >100 124 1.90 >100 >100125 <0.1 >100 >100

As shown in Table 2, the compound of the present invention has asuperior LSD1 inhibitory activity. In addition, the MAO-A inhibitoryactivity and MAO-B inhibitory activity of the compound of the presentinvention are low, and the compound of the present invention has aselective LSD1 inhibitory activity.

Experimental Example 3

Gad1 H3K4 Methylation Induction Activity in Rat Primary Culture Neurons

Experimental Method

Hippocampus and cerebral cortex were isolated from fetal SD rat atembryonic day 19, a cell suspension was prepared using Nerve CellDissociation Medium (SUMITOMO BAKELITE, MS-0006L), and plated on a polyL-lysine-coated 6-well plate (SUMITOMO BAKELITE, MS-0006L) at a densityof 900000 cells/well. Under the conditions of 37° C. and 5% CO₂, thecells were cultured in a neurobasal medium (Invitrogen, #211103049)containing B27 supplement (Invitrogen, #17504044, 1:50 dilution), 2 mML-glutamine (Lonza, #B76053), 100 U/mL penicillin/100 μg/mL streptomycin(Lonza, #17-602E), and 20 μg/mL gentamicin sulfate (Lonza, #17-519Z) for10 days.

Thereafter, the compound was added to final concentrations of 10 μM, thecells were further cultured for 3 days, and chromatinimmunoprecipitation was performed. Chromatin immunoprecipitation wasperformed by using ChIP-IT Express Enzymatic (Active Motif, #53009) andH3K4me2 antibody (Millipore, #07-030). The culture supernatant wasaspirated, ice-cold PBS was added, and the cell suspension was collectedon ice using CELL SCRAPER (IWAKI). The supernatant was removed bycentrifugation at 3000 rpm, 4° C. for 5 min. Lysis buffer (500 μL) wasadded to the precipitate, and the cells were lysed by incubating for 30min on ice. Thereafter, the suspension was centrifuged at 2400 g, 4° C.for 10 min, the supernatant was removed, the pellet was suspended incell lysis buffer [60 mM KCl, 15 mM NaCl, 5 mM MgCl₂, 0.1 mM EGTA, 15 mMTris-HCl (pH 7.6), 1.2 M sucrose, 0.5 mM DTT, protease inhibitor (Roche,#4693132)] (500 μL), and the suspension was centrifuged at 10000 g, 4°C. for 10 min. The supernatant was removed, and the pellet was suspendedin Digestion buffer (120 μL) and preincubated at 37° C. for 5 min.Shearing cocktail was added, and the mixture was incubated at 37° C. for20 min. 0.5 M EDTA (2.4 μL) was added, and the mixture was incubated for10 min on ice and centrifuged at 18000 rpm, 4° C. for 10 min. Thesupernatant was collected as a chromatin fraction and subjected toimmunoprecipitation.

Using the DNA obtained by the chromatin immunoprecipitation as atemplate, quantitative PCR of the Gad1 gene upstream genomic region wasperformed, and the measurement value was taken as the Gad1 H3K4me2level. The quantitative PCR was performed by ABI PRISM 7900HT SequenceDetection System (Applied Biosystems) using forward primer:5′-TGATCTTTTCCCTGCTGTCA-3′ (SEQ ID NO: 8), reverse primer:5′-TCCCATGAGTAATCCAGAACG-3′ (SEQ ID NO: 9), and SYBR Green Realtime PCRMaster Mix-Plus-(TOYOBO, #QPK-212). The Gad1 H3K4me2 induction by thecompound was expressed by the H3K4me2 level when the compound was added,as compared to the H3K4me2 level of the control (without addition of thecompound) as 100%.Gad1 H3K4me2 induction activity (%) (H3K4me2 induction expressed aspercentage of control)=(H3K4me2 level with addition of compound÷H3K4me2level without addition of compound)×100

The Gad1 H3K4me2 induction activity by each compound as measured by theabove-mentioned method is shown in Table 3.

TABLE 3 Gad1 H3K4me2 induction activity (%) Example No. 10 μM 102 153 82115 123 143 99 146 97 184 71 182 118 233

From the results of Table 3, it was clarified that the compound of thepresent invention has an inductive effect on H3K4 methylation.

Experimental Example 4

Evaluation of Blood Cell Number in Mouse

Experimental Method

Male ICR mice (hereinafter mice) were acclimated for at least one weekin a rearing facility. The mice were raised in a rearing room withcontrolled temperature and humidity under a 12:12 hour light-dark cycle,and allowed free ingestion of feed and water.

The compounds were suspended in 0.5% methylcellulose/0.5% citricacid/distilled water and orally administered. All compounds wererepeatedly administered to the mice at a dose of 1 mg/kg, 10 mg/kg or100 mg/kg (body weight) for 7 or 9 days. One day after the finaladministration of the compound, the whole blood was collected.

Using Sysmex XT-1800i (Sysmex Corporation), the white blood cell number,red blood cell number, and platelet number in the collected whole bloodper unit volume were measured. The influence of each compound on eachblood cell number was determined by calculating the number with the meanof each blood cell number of the mouse without administration of thecompound (0 mg/kg group), and the mean of each blood cell number in thewhole blood of a mouse with the administration of the compound. Thevalues of the blood cell numbers measured by the above-mentioned methodare shown in Table 4.

TABLE 4 Example 0 mg/kg 1 mg/kg 10 mg/kg 100 mg/kg No. Mean S.E. MeanS.E. Mean S.E. Mean S.E. White blood cells (10 cells) 102 457 71 335 40425 34 361 50 99 340 30 399 46 378 40 347 28 97 397 59 377 43 366 44 33234 71 275 15 275 29 276 20 323 16 82 322 17 403 47 424 51 329 21 84 31244 370 30 339 41 313 38 118 275 15 299 51 312 34 245 12 123 389 42 39047 368 22 380 24 104 375 22 373 44 397 28 — — 95 375 22 422 46 408 27 —— Red blood cells (10⁴ cells) 102 888 16 903 12 929 18 929 16 99 863 17892 17 915 20 876 19 97 902 12 902 12 890 25 929 18 71 830 32 873 23 81720 853 8 82 872 11 899 20 926 21 903 19 84 884 25 910 18 880 24 900 12118 830 32 853 17 907 19 881 13 123 829 13 846 14 854 13 866 7 104 883 8870 16 872 16 — — 95 883 8 888 15 898 12 — — Platelets (10³ cells) 1021401 53 1387 56 1499 43 1417 61 99 1468 71 1442 65 1380 49 1519 99 971466 22 1462 65 1483 78 1533 55 71 1148 63 1178 76 1197 67 1322 91 821389 35 1399 44 1445 38 1411 58 84 1515 60 1533 43 1627 58 1665 107 1181148 63 1051 71 1158 66 1176 60 123 1130 58 1086 79 1234 68 1333 75 1041345 33 1370 32 1404 77 — — 95 1345 33 1352 66 1482 66 — —

From the results of Table 4, it was clarified that the compound of thepresent invention reduces an influence on the white blood cell number,red blood cell number and platelet number.

Experimental Example 5

Evaluation of Hippocampal Distribution in Mouse

Experimental Method

Male ICR mice (hereinafter mice) were acclimated for at least one weekin a rearing facility. The mice were raised in a rearing room withcontrolled temperature and humidity under a 12:12 hour light-dark cycle,and allowed free ingestion of feed and water.

The compounds were suspended in 0.5% methylcellulose/0.5% citricacid/distilled water and orally administered. All compounds wereadministered to the mice at a dose of 10 mg/kg (body weight).

Blood samples were collected at 0.5 hr or 1 hr from compoundadministration, and the hippocampus was isolated simultaneously. Theplasma concentration and hippocampus concentration of each test compoundwere measured by the LC/MS/MS method, the ratio (hippocampus/plasmaconcentration ratio) was calculated, and distribution into hippocampuswas evaluated. The results are shown in Table 5.

TABLE 5 Concentration Ratio (μg/mL or μg/g) (hippo- time after Hippo-campus/ Example administration Plasma campus plasma) No. (h) Mean S.D.Mean S.D. Mean S.D. 102 1 0.348 0.008 0.104 0.021 0.298 0.062 99 1 2.9480.934 0.640 0.168 0.223 0.047 97 1 0.978 0.182 0.194 0.012 0.205 0.05171 1 0.229 0.027 0.082 0.015 0.358 0.063 82 1 1.327 0.115 0.170 0.0210.128 0.015 84 1 0.523 0.120 0.177 0.040 0.339 0.014 118 1 0.405 0.1130.151 0.022 0.384 0.061 123 0.5 1.107 0.123 0.369 0.089 0.333 0.070

As shown in Table 5, the compounds of the present invention were allconfirmed to have distributed into the hippocampus.

Formulation Example 1

A medicament containing the compound of the present invention as anactive ingredient can be produced, for example, according to thefollowing formulation.

1. Capsule

(1) compound obtained in Example 1 10 mg (2) lactose 90 mg (3)crystalline cellulose 70 mg (4) magnesium stearate 10 mg 1 capsule 180mg 

The total amount of the above-mentioned (1), (2) and (3) and 5 mg of (4)are blended, and the mixture is granulated. Thereto is added theremaining 5 mg of (4), and the whole is sealed in a gelatin capsule.

2. Tablet

(1) compound obtained in Example 1 10 mg (2) lactose 35 mg (3)cornstarch 150 mg  (4) crystalline cellulose 30 mg (5) magnesiumstearate  5 mg 1 tablet 230 mg 

The total amount of the above-mentioned (1), (2) and (3), 20 mg of (4)and 2.5 mg of (5) are blended, and the mixture is granulated. Theretoare added the remaining 10 mg of (4) and 2.5 mg of (5), and the mixtureis compression-molded to give a tablet.

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior LSD1 inhibitoryaction, and is useful as a medicament such as a prophylactic ortherapeutic agent for cancer, schizophrenia, developmental disorders,particularly diseases having intellectual disability (e.g., autisticspectrum disorders, Rett syndrome, Down's syndrome, Kabuki syndrome,fragile X syndrome, Kleefstra syndrome, neurofibromatosis type 1, Noonansyndrome, tuberous sclerosis), neurodegenerative diseases (e.g.,Alzheimer's disease, Parkinson's disease, spinocerebellar degeneration(e.g., dentatorubural pallidoluysian atrophy) and Huntington's disease(Huntington chorea)), epilepsy (e.g., Dravet syndrome) or drugdependence, and the like.

This application is based on patent application No. 2014-82057 filed inJapan, the entire contents of which are incorporated by referenceherein.

The invention claimed is:
 1. A method for the treatment of autisticspectrum disorders, in a mammal, comprising administering an effectiveamount of5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamideor a salt thereof to the mammal.